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PIVOTAL TRIALS IN OVARIAN
CANCER: WHAT HAS DEFINED THE
STANDARD OF CARE TO DATE?
The Typical Course of Advanced Ovarian Cancer1-5
*Around 5% of patients are primary treatment-refractory, meaning disease progressed during therapy or within 4 weeks after the last dose.
IDS=interval debulking surgery.
1. Ledermann JA et al. Ann Oncol. 2013;24(Suppl 6):vi24-vi32. 2. Giornelli GH. Springerplus. 2016;5(1):1197. 3. Pignata S et al. Ann Oncol. 2017;28(suppl_8):viii51-viii56. 4. du Bois A et al. Cancer.
2009;115(6):1234-1244. 5. Wilson MK et al. Ann Oncol. 2017;28(4):727-732.
First-Line
Treatment
Stage III, IV
First Response*
Surgery (primary or IDS)
+ primary or adjuvant chemotherapy
+/- bevacizumab
Second
Response/
Disease
Stabilisation
Patients for whom platinum is an
option, formerly ‘Platinum-Sensitive’
Progression >6 months after completion
of platinum-based chemotherapy
Patients for whom platinum is not an
option, formerly ‘Platinum-Resistant’
Progression <6 months after completion of
platinum-based chemotherapy
Relapse/
Progression
(100%)
Relapse/
Progression
(70%–80%)
Follow-up
Ovarian Cancer: Course of Disease
AGO=Arbeitsgemeinschaft Gynäkologische Onkologie; FIGO=International Federation of Gynecology and Obstetrics; PFS=progression-free survival.
1. du Bois A et al. Cancer. 2009;115(6):1234-1244. 2. Data from the AGO Study Group.
Adapted from a slide curtesy of Prof Frederik Marmé.
Time (months)
Progression-FreeSurvival
(3126patients/275events)(%)
21.8% relapse 0-6 months
after chemotherapy (resistant)
22.5% relapse within 6-12 months
after chemotherapy (partially sensitive)
0 120108 1322412 48 72 84 9636 60
100
0
70
50
30
10
90
60
40
20
80
31.6% relapse within 12-60 months
after chemotherapy (sensitive)
Primary
resistance
Secondary
resistance
Cure
Median PFS
18.2 months
21.8%
relapse within
6 months
54.1%
relapse after
> 6 months
31.6%
after > 12 months
24%
never relapse
FIGO IIB-IV: Individual patient data meta-analysis of three AGO phase 3 first-line trials (AGO Ovar 3, 5, 7)1,2
5 year
PFS 22.6%
Ovarian Cancer Is Not One Disease, Yet All Types are Treated the Same
Banerjee S et al. Clin Cancer Res. 2013;19(5):961-968.
Ovarian cancer
Epithelial Nonepithelial
High-grade
serous
Low-grade
serous
Mucinous Clear cell Endometrioid
Sex
cord-stromal
Others,
including
germ cell
TP53
BRCA1 and 2
NF1
RB1
CDK12
Homologous
recombination
repair genes
BRAF
KRAS
NRAS
ERBB2
KRAS
HER2
amplification
ARID1A
PIK3CA
PTEN
CTNNB1
PPP2R1α
ARID1A
PIK3CA
PTEN
PPP2R1α
MMR deficiency
Granulosa cell
FOXL2
Sertoll-Leydig cell
DICER1
Pathway alterations:
PI3K/RAS/NOTCH/FOXM1
Paclitaxel and carboplatin
Nonepithelial
Sex
cord-stromal
Others,
including
germ cell
Granulosa cell
FOXL2
Sertoli-Leydig cell
DICER1
First-Line Surgical Cytoreduction
• To date, 3 trials (EORTC 55971, CHORUS, JCOG0602) comparing primary chemotherapy with interval debulking surgery (NACT) and
primary debulking surgery followed by chemotherapy have shown no differences in PFS/OS3-5
– NB. Rate of no residual disease was relatively low in these studies
– Are there selected patients for whom one approach is preferable/better?
• TRUST trial ongoing to address role of radical surgery6
CI=confidence interval; HR=hazard ratio; NACT=neoadjuvant chemotherapy; NB=nota bene; OS=overall survival; PFS=progression-free survival.
1. du Bois A et al. Cancer. 2009;115(6):1234-1244. 2. Harter P et al. J Clin Oncol. 2017;35(15_suppl):5500. 3. Vergote I et al. N Engl J Med. 2010;363(10):943-953. 4. Kehoe S et al. Lancet.
2015;386(9990):249-257. 5. Onda T et al. Eur J Cancer. 2016;64:22-31. 6. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02828618. Accessed 25 September 2018.
HR (95% CI)
1-10 mm vs 0 mm: 2.52 (2.26; 2.81)
>10 mm vs 1-10 mm: 1.36 (1.24; 1.50)
Log-rank P<0.0001
100
75
50
25
0
0 12 24 36 48 60 72 84 96 108 120 132 144
OverallSurvival(%)
0 mm
1-10 mm
>10 mm
• Surgical cytoreduction is the strongest
stage-related independent prognostic factor1
• Aim for no residual disease1
• Lymphadenectomy of non-enlarged lymph nodes
in patients with advanced ovarian cancer and
complete resection should be omitted2
Overall Survival1
Time (months)
First-Line Systemic Neoadjuvant Chemotherapy (NACT)
Wright AA et al. J Clin Oncol. 2016;34(28):3460-3473.
Surgery after 3-4 cycles recommended
Weekly dose-dense chemotherapy can be delivered successfully as first-line epithelial ovarian cancer treatment without
substantial toxicity increase; it does not significantly improve PFS compared to standard 3-weekly chemotherapy
ICON8 Progression-Free Survival
First-Line Chemotherapy Standard of Care:
Carboplatin and Paclitaxel
CI=confidence interval; HR=hazard ratio; PFS=progression-free survival.
Clamp AR et al. Presented at: ESMO Annual Meeting; 2017.
Standard
(n=522)
Weekly
paclitaxel
(n=523)
Weekly
carbo-paclitaxel
(n=521)
Progressions 330 (63%) 335 (64%) 338 (65%)
Median PFS, mo 17.9 20.6 21.1
Log rank
(vs standard)
P=0.45 P=0.56
HR vs Standard
(97.5% CI)
0.92
(0.77–1.09)
0.94
(0.79–1.12)
Restricted
means
24.4 months 24.9 months 25.3 months
522 318 1354471 198 92 59 32250 130Standard
No. at risk
523 17383489 210 92 59 28279 144Weekly paclitaxel 3 0
521 15385468 208 99 66 33281 153Weekly carbo-paclitaxel 6 0
Time from Randomisation (months)
0 6054 66126 24 36 42 4818 30
1.00
0.00
0.50
0.25
0.75
Standard
Weekly paclitaxel
Weekly carbo-paclitaxel
Progression-FreeSurvival(proportion)
First-Line Bevacizumab: Progression-Free Survival
Bev=bevacizumab.
1. Burger RA et al. N Engl J Med. 2011;365(26):2473-2483. 2. Perren TJ et al. N Engl J Med. 2011;365(26):2484-2496.
GOG 2181
625 8199 33Chemotherapy
625 6219 29Bev initiation
623 8254 38Bev throughout
ICON72
No. at risk
764 25693 216Chemotherapy 464 91
764 19715 263Bevacizumab 585 73
No. at risk
100
0
0 30
Progression-FreeSurvival(%)
Time from Randomisation (months)
Bevacizumab
Chemotherapy
19.0 months
17.3 months
3 6 9 12 15 18 21 24 27
75
50
25
Time from Randomisation (months)
1.0
0.6
0.4
0.0
0 2 14 22 28 36
Progression-FreeSurvival
(proportion)
0.2
0.8
0.9
0.7
0.5
0.3
0.1
4 6 8 10 12 16 18 20 24 26 30 32 34
Bev initiation
Bev throughout
Chemotherapy
14.1 months
10.3 months
Advanced
epithelial ovarian
cancer
Paclitaxel +
carboplatin + placebo Placebo
Placebo
(Bev Initiation)
Bevacizumab
(Bev throughout)
Paclitaxel + carboplatin
+ bevacizumab
Cycles 1–6;
+ bevacizumab at cycle 2
Until disease progression
or up to 22 cycles
Advanced
epithelial ovarian
cancer
Paclitaxel +
carboplatin
Bevacizumab
Paclitaxel + carboplatin
+ bevacizumab
Cycles 1–6 Until disease progression
or 12 cycles
First-Line Bevacizumab: Overall Survival
No overall survival benefit was demonstrated;1,2 bevacizumab was approved by the EMA and
FDA for first-line treatment in December 2011 and June 2018, respectively4,5
Bev=bevacizumab; CI=confidence interval; EMA=European Medicines Agency; FDA=US Food and Drug Administration; HR=hazard ratio.
1. Burger RA et al. N Engl J Med. 2011;365(26):2473-2483. 2. Perren TJ et al. N Engl J Med. 2012;365(26):2484-2496. 3. Oza AM et al. Lancet Oncol. 2015;16(8):928-936. 4. Roche Media Release.
https://www.roche.com/dam/jcr:47093e15-51d4-47ca-9bbb-a082d7bf0dd1/en/med-cor-2011-12-23-e.pdf. Accessed 5 October 2018. 5. Roche Media Release.
https://www.roche.com/dam/jcr:01d38b33-167d-46a6-87f9-4e5f3f0340d3/en/20180613-MR-Avastin_FDA_en.pdf. Accessed 5 October 2018.
GOG 2181
1.0
0.8
0.6
0.4
0.2
0.0
0 6 12 18 24 30 36 42 48
Time from Randomisation (months)
OverallSurvival(proportion)
625 442 173 46Chemotherapy
No. at risk
625 432 162 39Bev initiation
623 437 171 40Bev throughout
Chemotherapy
Bevacizumab initiation
Bevacizumab throughout
156 (25.0)
150 (24.0)
138 (22.2)
No. of events (%)
ICON72
100
75
50
25
0
0 3 6 12 21 30
Time from Randomisation (months)
OverallSurvival(%)
272418159
No. at risk
764Standard
chemotherapy
724 652 33159368
764Bevacizumab 737 678 40162404
Standard chemotherapy
Bevacizumab
ICON7 subgroup, high risk: residual
disease >1 cm/Stage IV
ICON73
1.00
0.75
0.50
0.25
0
0 6 12 24 42 60
Time from Randomisation (months)
OverallSurvival(proportion)
5448363018
Standard chemotherapy
Bevacizumab
High risk: HR=0.78
(95% CI, 0.63–0.97)
66% events
Non-high risk: HR=1.14
(95% CI, 0.93–1.40)
37% events
Interaction: P=0.01
Need to improve QoL, PFS, TFST, TSST, OS, and the cure rate
Delay the psychological burden of disease progression
Delay the physical symptoms associated with progressive disease
The Need
Surgery (primary or IDS) with carboplatin and paclitaxel
(+/- bevacizumab) is the current standard of care
Intraperitoneal, HIPEC remains an area for further studies
The Current
Standard
Factors to consider: age, performance status, comorbidities,
extent of surgery, histology, molecular markers (eg, BRCA, HRD)
Other
Factors
Unmet Needs for Patients With Newly-Diagnosed Ovarian Cancer
There is a need for additional safe and effective maintenance options following
completion of first-line surgery and chemotherapy to improve patient outcomes
HIPEC=hyperthermic intraperitoneal chemotherapy; HRD=homologous recombination deficiency; IDS=interval debulking surgery; OS=overall survival; PFS=progression-free survival; QoL=quality of
life; TFST=time to first subsequent therapy or death; TSST=time to second subsequent therapy or death.
The Typical Course of Advanced Ovarian Cancer1-5
*Around 5% of patients are primary treatment-refractory, meaning disease progressed during therapy or within 4 weeks after the last dose.
IDS=interval debulking surgery.
1. Ledermann JA et al. Ann Oncol. 2013;24(Suppl 6):vi24-vi32. 2. Giornelli GH. Springerplus. 2016;5(1):1197. 3. Pignata S et al. Ann Oncol. 2017;28(suppl_8):viii51-viii56. 4. du Bois A et al. Cancer.
2009;115(6):1234-1244. 5. Wilson MK et al. Ann Oncol. 2017;28(4):727-732.
First-Line
Treatment
Stage III, IV
First Response*
Surgery (primary or IDS)
+ primary or adjuvant chemotherapy
+/- bevacizumab
Follow-up
Second
Response/
Disease
Stabilisation
Patients for whom platinum is an
option, formerly ‘Platinum-Sensitive’
Progression >6 months after completion
of platinum-based chemotherapy
Patients for whom platinum is not an
option, formerly ‘Platinum-Resistant’
Progression <6 months after completion of
platinum-based chemotherapy
Relapse/
Progression
(100%)
Relapse/
Progression
(70%–80%)
An Example of the Course of Advanced Ovarian Cancer
for an Individual Patient
CA–125level
FIRST LINE: surgery, carboplatin
+ paclitaxel +/- bevacizumab
FIFTH LINE:
carboplatin +
gemcitabine
Bowel
obstruction
Death
SECOND LINE:
carboplatin + PLD
followed by PARPi
THIRD LINE:
weekly
paclitaxel
FOURTH
LINE:
clinical trial
Symptoms
PFS PFS PFS PFS PFS
Time
PARPi=PARP inhibitor; PFS=progression-free survival; PLD=pegylated liposomal doxorubicin.
Ledermann JA et al. Ann Oncol. 2013;24(Suppl 6):vi24-vi32.
Treatment Options for Patients With
Relapsed Ovarian Cancer for
Whom Platinum is an Option
Combination vs Single-Agent Platinum Chemotherapy for Patients
With Relapsed Ovarian Cancer for Whom Platinum is an Option
Combination platinum chemotherapy improves OS and PFS compared with single-agent platinum chemotherapy
CI=confidence interval; HR=hazard ratio; IV=instrumental variables; OS=overall survival; PFS=progression-free survival.
Raja FA et al. Ann Oncol. 2013;24(12):3028-3034.
Study Weight
Hazard Ratio
IV, Random, (95% CI)
Hazard Ratio
IV, Random, 95% CI
ICON and AGO 2003 44.8% 0.81 (0.69–0.97)
Pfisterer et al 2006 35.1% 0.96 (0.75–1.23)
Alberts et al 2007 12.7% 0.69 (0.39–1.21)
González-Mart. et al 2005 7.5% 0.39 (0.18–0.84)
Total (95% CI) 100.0% 0.80 (0.64–1.00)
Heterogeneity: Tau2=0.02; Chi2=5.44, df=3 (P=0.14); I2=45%
Test of overall effect: Z=1.96 (P=0.05)
Study Weight
Hazard Ratio
IV, Random, (95% CI)
Hazard Ratio
IV, Random, 95% CI
ICON and AGO 2003 46.9% 0.75 (0.65–0.87)
Pfisterer et al 2006 33.7% 0.72 (0.58–0.90)
Alberts et al 2007 9.6% 0.52 (0.31–0.88)
González-Mart. et al 2005 9.8% 0.45 (0.27–0.76)
Total (95% CI) 100.0% 0.68 (0.57–0.81)
Heterogeneity: Tau2=0.01; Chi2=4.70, df=3 (P=0.19); I2=36%
Test of overall effect: Z=4.30 (P<0.0001)
OverallSurvival
Progression-Free
Survival
0.1 0.2 0.5 1 2 5 10
Favors combination Favors single agent
0.1 0.2 0.5 1 2 5 10
Favors combination Favors single agent
HR=0.8
HR=0.68
Combinations for Patients With Relapsed Ovarian Cancer
for Whom Platinum is an Option
Trial Regimen Median PFS (months) Median OS (months)
ICON41 Platinum chemotherapy/paclitaxel 12.0 29.0
CALYPSO2,3 Carboplatin/paclitaxel 9.4 33.0
CALYPSO2,3 Carboplatin/PLD 11.3 30.7
OVA-3014 Trabectedin/PLD 7.3 20.5*
OVAR 2.55 Carboplatin/gemcitabine 8.6 18.0
OCEANS (control)6 Carboplatin/gemcitabine 8.4 35.2†
OCEANS-bevacizumab6 Carboplatin/gemcitabine/bevacizumab 12.4 33.3†
GOG 2137 Carboplatin/paclitaxel/bevacizumab 13.8 42.2
*Based on an interim analysis.
†These data remain immature, with a high degree of censoring beyond month 18 and a longer-than-expected median OS in both arms.
OS=overall survival; PFS=progression-free survival; PLD=pegylated liposomal doxorubicin.
1. Parmar MK et al. Lancet. 2003;361(9375):2099-2106. 2. Pujade-Lauraine E et al. J Clin Oncol. 2010;28(20):3323-3329. 3. Wagner U et al. Br J Cancer. 2012;107(4):588-591. 4. Monk BJ et al. J Clin
Oncol. 2010;28(19):3107-3114. 5. Pfisterer J et al. J Clin Oncol. 2006;24(29):4699-4707. 6. Aghajanian C et al. J Clin Oncol. 2012;30(17):2039-2045. 7. Coleman RL et al. Lancet Oncol.
2017;18(6):779-791.
Chemotherapy + Bev
Bevacizumab for Patients With Relapsed Ovarian Cancer
for Whom Platinum is an Option
2 positive trials: improvement in progression-free survival, first platinum-sensitive relapse
Bevacizumab is administered in combination with either carboplatin and gemcitabine for 6 cycles and up to 10 cycles or
in combination with carboplatin and paclitaxel for 6 cycles and up to 8 cycles, followed by continued use of
bevacizumab as a single agent until disease progression3
Carboplatin + Gemcitabine +/- Bevacizumab Carboplatin + Paclitaxel +/- Bevacizumab
GOG 213: PFS2 GOG213: OS2
HR=0.628; P<0.0001 HR=0.829; P<0.0056HR=0.48; P<0.0001
Progression-freesurvival(%)
Time from Randomisation (months)No. at risk
(number censored)
Chemotherapy
Chemotherapy + Bev
337 (0) 125 (15) 40 (16) 20 (17) 12 (23) 5 (28)
337 (0) 201 (7) 84 (7) 46 (10) 16 (27) 9 (32)
Progression-freesurvival
(proportion)
100
80
60
40
20
0
0 12 24 36 48 60
100
80
60
40
20
0
12 24 36 48 600
Overallsurvival(%)
Time from Randomisation (months)
No. at risk
(number censored)
Chemotherapy
Chemotherapy + Bev
337 (0) 303 (15) 234 (17) 152 (30) 69 (77) 18 (109)
337 (0) 306 (8) 253 (9) 183 (20) 75 (82) 28 (110)
Chemotherapy
Chemotherapy + Bev
The recommended dose of bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion.
Bev=bevacizumab; HR=hazard ratio; OS=overall survival; PFS=progression-free survival.
1. Aghajanian C et al. J Clin Oncol. 2012;30(17):2039-2045. 2. Coleman RL et al. Lancet Oncol. 2017;18(6):779-791. 3. Avastin (Summary of Product Characteristics). Roche; 2018.
OCEANS: PFS1
Chemotherapy
Chemotherapy + Bev
1.0
Time from Randomisation (months)
No. at risk
Chemotherapy
Chemotherapy + Bev
0.8
0.6
0.4
0.2
0 6 12 18 24 30
242 177 45 11 3 0
242 203 92 33 11 0
Chemotherapy
Carboplatin + Paclitaxel +/- Bevacizumab
Treatment Options for Patients With
Relapsed Ovarian Cancer for
Whom Platinum is Not an Option
• Weekly paclitaxel (+/- bevacizumab)
• Pegylated liposomal doxorubicin (PLD) (+/- bevacizumab)
• Carboplatin and gemcitabine,* gemcitabine alone
• Weekly carboplatin/paclitaxel
• Topotecan (+/- bevacizumab)
• Hormonal therapy (aromatase inhibitors, tamoxifen)
• Metronomic cyclophosphamide
• Olaparib (BRCA-mutated, 3 or more prior lines)
Non-Trial Options for Patients With Relapsed Ovarian Cancer
for Whom Platinum Is Not an Option
*Consider carboplatin rechallenge in platinum-resistant disease depending on platinum-free interval.
These select treatment options represent the speaker’s personal approach to treating patients with relapsed ovarian cancer for whom platinum is not an option.
AURELIA: Practice Changing Trial
≤2 prior lines, Exclusion: platinum-refractory, prior (sub)obstruction, or bowel involvement
N=360, randomised 1:1
Bevacizumab for Patients With Relapsed Ovarian Cancer
for Whom Platinum Is Not an Option
Improved PFS by adding bevacizumab to non-platinum based chemo + QoL benefit in symptomatic patients
60
50
40
30
0
Substantial Symptoms
at Baseline
Patientswith
≥15%Improvement(%)
20
10
Ascites at Baseline
12.7
29.6
44.0
Diff: 16.9%
95% CI, 6.1–27.6
Diff: 39.9%
95% CI, 23.9–55.9
4.1
(n=118)(n=115) (n=49) (n=50)
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24
Time (months)
Progression-FreeSurvival
(probability)
182 93 37 20 8 1 1 0 0Chemo
No. at risk
179 140 88 49 18 4 1 1 0Chemo + Bev
3.4 6.7
Progression-Free Survival1
Chemo Chemo + Bev
Median PFS, mo 3.4 6.7
HR (95% CI) 0.48 (0.38–0.60)
P value P<0.001
Bev=bevacizumab; CI=confidence interval; diff=difference; PFS=progression-free survival; QoL=quality of life.
1. Pujade-Lauraine E et al. J Clin Oncol. 2014;32(13):1302-1308. 2. Stockler MR et al. J Clin Oncol. 2014;32(13):1309-1316.
Patient-Reported Outcomes2
Chemo
Chemo + Bev
Bevacizumab for Patients With Relapsed Ovarian Cancer
for Whom Platinum Is Not an Option
Improved PFS and ORR by adding bevacizumab to single-agent chemotherapy was observed across all chemotherapy cohorts
60
50
40
20
0
Paclitaxel cohort Topotecan cohort
ORR(RECIST,CA-125
criteria,orboth)(%)
30
10
PLD cohort
Diff: 22.9
95% CI, 3.9-41.8
51.7
28.8
18.37.9 22.8
3.3
Diff: 10.4
95% CI, -2.4–23.2
Diff: 19.5
95% CI, 6.7-32.3
1.00
0.75
0.50
0.25
0
0 3 6 9 12 15 18 21 24
Time (months)
Progression-FreeSurvival
(proportion)
HR = 0.46
(95% CI, 0.30–0.71)
3.9
10.4
1.00
0.75
0.50
0.25
0
0 3 6 9 12 15 18
Time (months)
Progression-Free
Survival(proportion)
HR=0.57
(95% CI, 0.39-0.83)5.4
3.5
1.00
0.75
0.50
0.25
0
0 3 6 9 12 15
Time (months)
Progression-FreeSurvival
(proportion)
HR = 0.32
(95% CI, 0.21-0.49)
2.1
5.8
Chemo
Chemo + Bev
Bev=bevacizumab; CI=confidence interval; diff=difference; ORR=overall response rate; PFS=progression-free survival; PLD=pegylated liposomal doxorubicin; RECIST=Response Evaluation Criteria
In Solid Tumours.
Poveda AM et al. Presented at: ESMO Annual Meeting; 2012.
PFS: Paclitaxel Cohort PFS: Topotecan Cohort
PFS: PLD Cohort Overall Response Rates
AURELIA: Practice Changing Trial
≤2 prior lines, Exclusion: platinum-refractory, prior (sub)obstruction, or bowel involvement
N=360, randomised 1:1
The Importance of
BRCA Testing
Beginning with a tumour test rather than a germline test:
• Fewer patients will require two rounds of BRCA testing (a greater number of women with ovarian cancer will test
negative on germline testing than will test positive on tumour testing). More cost-effective?
• Consent may be perceived as more straightforward
• Potential risk of not obtaining an accurate result (technical issues): missing a BRCA mutation
BRCA Testing (Germline or Tumour): Standard of Care1-5
Current perspectives on recommendations for BRCA genetic testing in ovarian cancer patients.
1. Vergote I et al. Eur J Cancer. 2016;69:127-134. 2. NCCN Guidelines. https://www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf. Accessed 24 September 2018. 3. SGO.
https://www.sgo.org/clinical-practice/guidelines/genetic-testing-for-ovarian-cancer/. Accessed 24 September 2018. 4. ASCO. https://www.asco.org/practice-guidelines/cancer-care-
initiatives/genetics-toolkit/assessing-your-patient%E2%80%99s-hereditary. Accessed 24 September 2018. 5. Ledermann JA et al. https://www.esmo.org/Guidelines/Gynaecological-Cancers/Newly-
Diagnosed-and-Relapsed-Epithelial-Ovarian-Carcinoma/eUpdate-Treatment-Recommendations. Accessed 24 September 2018.
A patient with ovarian
cancer who is BRCA
Wild type on germline
testing would need a
subsequent tumour
testing to establish
whether or not she has a
somatic BRCA mutation
to access olaparib
A patient with ovarian
cancer who has a BRCA
mutation identified from
tumour testing would
need subsequent
germline testing to
determine whether
there are implications
for her relatives
Germline test
Tumour test
Negative
Tumour test
Germline test
Positive
Need to improve response rate, PFS, TFST, TSST, OS, and the cure rate
Delay the psychological burden of disease progression
Delay the physical symptoms associated with progressive disease
Why?
All newly diagnosed patients following first-line therapy AND
All patients who have relapsed
Who?
A therapy that is effective and has convenient administration, limited
impact on QoL, and limited toxicity
What?
Unmet Needs for Patients With Newly Diagnosed and
Relapsed Ovarian Cancer
Maintenance PARP inhibitors are a significant step forward in tackling the unmet need
for women with ovarian cancer
OS=overall survival; PFS=progression-free survival; QoL=quality of life; TFST=time to first subsequent therapy or death; TSST=time to second subsequent therapy or death.
PARP Inhibitors Trap PARP, Preventing the Repair of SSBs Which
Are Then Converted to DSBs
24
Increase in double-
strand breaks in
replicating cells
Double-strand breaks
Trapped PARP on
single-strand breaks
PARP
PARPi
DSB=double-strand break; PARPi=PARP inhibitor; SSB=single-strand break.
O’Connor MJ. Mol Cell. 2015;60(4):547-560.
In HRD Cells, Where Deficiencies in DSB Repair Exist, the Cells
Cannot Cope With the Increase in DSBs and This Leads to Cell Death
25
HRR-deficient cancer cell
Increase in double-
strand breaks in
replicating cells
Trapped PARP on
single-strand breaks
Double-strand breaks
Normal cell
Repair of double-strand
breaks via the HR
pathway and cell survival
PARP
PARPi
✓
Reliance on error-prone
pathways leads to DNA damage
accumulation and cell death 
DSB=double-strand break; HR=homologous recombination; HRD=HR deficient; HRR=HR repair.
O’Connor MJ. Mol Cell. 2015;60(4):547-560.
Rationale for PARP Inhibitors in Ovarian Cancer:
High-Grade Serous Ovarian Cancer Biology
HRR=homologous recombination repair.
Hollis RL et al. Cancer Biol Med. 2016;13:236-247.
26
8%
6%
4%
3%
11%
6%
<5%
14%
7%
20%
17%
Germline BRCA1
Germline BRCA2
Somatic BRCA1
Somatic BRCA2
BRCA1 methylation
EMSY amplification
Other HRR genes
CCNE1 amplification
PTEN loss
RB1 loss
NF1 loss
TP53
mutation
HRR Proficient HRR Deficient
Olaparib1-8 Niraparib9,10 Rucaparib11,12
Indications
EU, Australia, Canada
Japan, Taiwan & China:
• Maintenance treatment of PSR
ovarian cancer +/- BRCAm
US & India:
• Maintenance treatment of PSR
ovarian cancer +/- BRCAm
• gBRCAm ovarian cancer after ≥3
lines of chemotherapy
EU & US:
• Maintenance treatment of PSR
ovarian cancer +/- BRCAm
EU:
• BRCAm ovarian cancer after
≥2 lines of chemotherapy
US:
• Maintenance treatment of PSR
ovarian cancer +/- BRCAm
• BRCAm ovarian cancer after ≥2
lines of chemotherapy
Dosing
300 mg (2 tablets*) BID
400 mg (8 capsules*) BID
300 mg (3 capsules) QD 600 mg (2 tablets) BID
Additional
Indications
US, Australia, Canada, India & Japan:
• gBRCAm, HER2-ve mBC following
chemotherapy
PARP Inhibitors Approved for Ovarian Cancer
*Olaparib capsules and tablets are not interchangeable.
BID=twice daily; BRCAm=BRCA mutated; gBRCAm=germline BRCAm; HER2=human epidermal growth factor receptor 2; QD=once daily; PSR=platinum-sensitive relapsed.
1. LYNPARZA (prescribing information). AstraZeneca; 2018. 2. LYNPARZA (SmPC). AstraZeneca, 2018. 3. LYNPARZA (product monograph). AstraZeneca; 2018. 4. AstraZeneca [press release].
https://www.astrazeneca.com/media-centre/press-releases/2018/lynparza-receives-approval-in-japan-for-the-treatment-of-advanced-ovarian-cancer-19012018.html. Accessed 31 August 2018. 5. Biocentury. China
approves Lynparza in ovarian cancer. https://www.biocentury.com/bc-extra/company-news/2018-08-23/china-approves-lynparza-ovarian-cancer. Accessed 31 August 2018. 6. Astrazeneca Pharma India Ltd.
https://www.bseindia.com/xml-data/corpfiling/AttachLive/96ccdd40-16ae-46d0-b332-6e8991aa8bc9.pdf. Accessed 31 August 2018 7. AstraZenenca (press release). https://www.astrazeneca.com/media-
centre/press-releases/2018/lynparza-approved-in-japan-for-brca-mutated-metastatic breast-cancer-02072018.html. Accessed 31 August 2018. 8. LYNPARZA olaparib 150 mg film coated tablet blister pack.
https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=2D8DEBA19DE565EFCA2582E2004244D5&agid=(PrintDetailsPublic)&actionid=1. Accessed 31 August 2018 9. ZEJULA (summary
of product characteristics). Tesaro; 2017. 10. ZEJULA (prescribing information). Tesaro; 2018. 11. RUBRACA (summary of product characteristics). Clovis; 2018. 12. RUBRACA (prescribing information). Clovis; 2018.
27
Veliparib and talazoparib are not approved for use in ovarian cancer.
The ENGOT-ov16/NOVA
and ARIEL3 Trials
28
ENGOT-ov16/NOVA: Study Design
29
Stratification factors:
• TTP on penultimate platinum therapy (6 to <12 months vs ≥12 months)
• Prior bevacizumab treatment
• Best response (complete or partial) during the last platinum regimen
Niraparib
300 mg QD until
progression/toxicity
Placebo
QD until
progression/toxicity
Patients
• PSR high grade serous ovarian* cancer
• ≥2 lines of platinum-based therapy
• Achieved a CR or PR
• No measurable disease <2 cm
• CA 125 in the normal range (or
decreased by more than 90% during last
regimen and stable for at least 7 days)
gBRCAm
Randomise 2:1
n=203
Non-gBRCAm*
Randomise 2:1
n=350
Niraparib
300 mg QD until
progression/toxicity
Placebo
QD until
progression/toxicity
*Includes sBRCAm patients.
CR=complete response; gBRCAm=germline BRCA mutated; PR=partial response; PSR=platinum-sensitive relapsed; QD=once daily; TTP=time to progression.
1. Mirza MR et al. N Engl J Med. 2016;375(22):2154-2164. 2. Mirza MR et al. N Engl J Med. 2016;375(22):2154-2164. Supplementary appendix.
No. at Risk
Niraparib 138 125 107 98 89 79 63 44 28 26 16 3 1
Placebo 65 52 34 21 12 8 6 2 2 2 1 1 0
ENGOT-ov16/NOVA: BICR-Assessed Progression-Free Survival
30
BICR=blinded independent central review; CI=confidence interval; gBRCAm=germline BRCA mutated; HR=hazard ratio; PFS=progression-free survival.
1. Mirza MR et al. N Engl J Med. 2016;375(22):2154-2164. 2. Center for Drug Evaluation and Research. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208447Orig1s000
MultidisciplineR.pdf. Accessed 13 September 2018.
24
gBRCAm1
100
75
50
25
0
Time from Randomisation (months)
121086420 14 16 18 20 22
Progression-FreeSurvival(%)
Niraparib
Placebo
Niraparib Placebo
Median, mo 21.0 5.5
HR (95% CI) 0.27 (0.17–0.41)
Median, mo 14.8 5.5
HR (95% CI) 0.27 (0.18–0.40)
BICR assessed1
Investigator
assessed2
No. at Risk
Niraparib 234 188 145 113 88 75 57 41 23 21 16 7 3
Placebo 116 88 52 33 23 19 10 8 4 4 3 1 1
Time from Randomisation (months)
Non-gBRCAm1
100
75
50
25
0
121086420 14 16 18 20 22 24
Progression-FreeSurvival(%)
Niraparib
Placebo
Niraparib Placebo
Median, mo 9.3 3.9
HR (95% CI) 0.45 (0.34–0.61)
P value P<0.001
BICR assessed1
ARIEL3: Study Design
31
Patients
• PSR high-grade serous or
endometrioid epithelial
ovarian cancer
• ≥2 prior platinum-based
treatment regimens
• ≤1 non-platinum
chemotherapy regimen
• CR or PR to last course of
chemotherapy
Rucaparib
600 mg BID until
progression/toxicity
n=375
Primary endpoint: Investigator-
assessed PFS in:
• tBRCAm
• HRD
• Intent-to-treat population
Secondary endpoints:
• PFS (BICR)
• PROs
• Population PK
• Overall survival
• Safety and tolerability
Placebo
BID until
progression/toxicity
n=189
Randomise 2:1
N=564
Stratification factors:
• HRR gene status
• Time to progression with penultimate
platinum therapy
• Response to last platinum
BICR=blinded independent central review; BID=twice daily; CR=complete response; HRD=homologous recombination deficient; PFS=progression-free survival; PK=pharmacokinetics; PR=partial
response; PRO=patient-reported outcome; PSR=platinum-sensitive relapsed; tBRCAm=tumour BRCA mutated.
Coleman RL et al. Lancet. 2017;390(10106):1949-1961.
The primary endpoint was investigator-assessed PFS (per RECIST)
• BRCAm and LOH in tumour samples were measured using Foundation Medicine’s T5 NGS assay
32
ARIEL-3: Primary Endpoint and Step-Down Analysis
Germline or somatic
BRCA mutation
Germline or somatic
BRCA mutation
+
BRCA wild-type/LOH high
(≥16% genomic
LOH prespecified)
Germline or somatic BRCA mutation
+
BRCA wild-type/LOH high
+
BRCA wild-type/LOH low
+
BRCA wild-type/LOH indeterminate
If
significant*
BRCAm HRD+
ITT
(all comers)
If
significant*
*Investigator-assessed PFS at a one-sided 0.025 significance level.
Visit cutoff date for all analyses: 15 April 2017.
BRCAm=BRCA mutated; HRD=homologous recombination deficient; ITT=intent-to-treat; LOH=loss of heterozygosity.
Coleman RL et al. Lancet. 2017;390(10106):1949-1961.
No. at Risk
(censored)
Niraparib 130 (0) 93 (14) 63 (21) 35 (37) 15 (51) 3 (60) 0 (63)
Placebo 66 (0) 24 (5) 6 (7) 3 (8) 1 (9) 0 (10) 0 (10)
ARIEL-3: Progression-Free Survival of Patients With BRCAm
33
BID=twice daily; BRCAm=BRCA mutated; CI=confidence interval; HR=hazard ratio.
Coleman RL et al. Lancet. 2017;390(10106):1949-1961.
Time from Randomisation (months)
36
Primary Endpoint: Investigator-Assessed PFS
181260 24 30
100
75
50
25
0
Rucaparib
Placebo
Progression-FreeSurvival(%)
Rucaparib
BID
Placebo
BID
Median, mo 16.6 5.4
HR (95% CI) 0.23 (0.16–0.34)
Median, mo 26.8 5.4
HR (95% CI) 0.20 (0.13–0.32)
Investigator
assessed
BICR
assessed
No. at Risk
(censored)
Niraparib 375 (0) 228 (36) 128 (61) 65 (93) 26 (123) 5 (136) 0 (141)
Placebo 118 (0) 63 (12) 7 (18) 7 (18) 2 (20) 1 (21) 0 (22)
No. at Risk
(censored)
Niraparib 236 (0) 161 (20) 96 (36) 54 (60) 21 (86) 5 (97) 0 (102)
Placebo 118 (0) 40 (10) 11 (12) 6 (14) 1 (16) 0 (17) 0 (17)
ARIEL-3: Investigator-Assessed PFS of HRD+ Patients and
the ITT Population
34
Treatment
PFS
Median, mo
HR (95% CI)
P value
Rucaparib
(n=375)
10.8 0.36
(0.30–0.45)
P<0.0001
Placebo
(n=189)
5.4
Treatment
PFS
Median, mo
HR (95% CI)
P value
Rucaparib
(n=236)
13.6 0.32
(0.24–0.42)
P<0.0001
Placebo
(n=118)
5.4
BRCAm=BRCA mutated; CI=confidence interval; HR=hazard ratio; HRD=homologous recombination deficient; ITT=intent-to-treat; PFS=progression-free survival.
Coleman RL et al. Lancet. 2017;390(10106):1949-1961.
Time from Randomisation (months)
ITT
181260 24 30 36
100
75
50
25
0
Rucaparib
Placebo
Progression-FreeSurvival(%)
HRD+
Time from Randomisation (months)
181260 24 30 36
100
75
50
25
0
Rucaparib
Placebo
Progression-FreeSurvival(%)
Summary
35
PARPi therapy is one of the most important advances for ovarian cancer patients in the past decades
Maintenance with niraparib or rucaparib significantly improves progression-free survival after platinum response
in platinum-sensitive relapsed ovarian cancer. However, no direct comparison is possible due to differences in
study designs1,2
BRCAm patients benefit most, but no predictive NGS test is sensitive enough to rule out the benefit for BRCAwt
patients who have platinum-sensitive relapsed ovarian cancer1,2
Treatment-emergent adverse events with niraparib or rucaparib were generally managed with dose
modifications (67% and 55%, respectively), and the rate of discontinuation was low (15% and 13%, respectively)1,2
Note: In the absence of head-to-head data between PARPi efficacy and safety comparisons between PARPi are not to be made or communicated.
BRCAm=BRCA mutated; BRCAwt=BRCA wild type; NGS=next-generation sequencing; PARPi=PARP inhibitor.
1. Mirza MR et al. N Engl J Med. 2016;375(22):2154-2164. 2. Coleman RL et al. Lancet. 2017;390(10106):1949-1961.
SOLO-2, a phase 3 study, was designed to provide additional evidence for the benefit of olaparib
maintenance therapy in patients with BRCAm PSR ovarian cancer1,2
• SOLO-2 reported data on the new film-coated tablet
formulation of olaparib1-3
• The tablet formulation used in SOLO-2 was chosen
based on data from Study 244
• The recommended tablet dose was 300 mg
administered as 2 x 150-mg tablets, twice daily4
36
SOLO-2: Study Design
Placebo
n=99
Olaparib 300 mg
BID tablets
n=196
Primary endpoint:
Investigator-assessed PFS
2:1 randomisation
Patients:
• PSR SOC and BRCA1/2 mutation
• ≥2 prior lines of platinum therapy
• CR or PR to most recent therapy1
BID=twice daily; BRCAm=BRCA mutated; CR=complete response; PFS=progression-free survival; PR=partial response; PSR=platinum-sensitive relapsed; SOC=standard of care.
1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01874353. Accessed 24 September 2018. 2. Pujade-Lauraine E et al. Lancet Oncol. 2017;18(9):1274-1284. 3. Ledermann J et al. N Engl J
Med. 2012;366:1382–1392. 4. Mateo J et al. Target Oncol. 2016;11(3):401–415.
Risk of progression or death during the study was reduced by 70% for patients taking olaparib vs placebo1.2
37
SOLO-2: Investigator-Assessed Progression-Free Survival
36
Olaparib
Placebo
No. at Risk
Investigator-assessed PFS at 63% maturity. Median follow-up for PFS was 22.1 months in the olaparib group and 22.2 months for placebo. Full assessment set N=295. Data cutoff: 9/19/2016.
BID=twice daily; CI=confidence interval; HR=hazard ratio; PFS=progression-free survival.
1. Pujade-Lauraine E et al. Lancet Oncol. 2017;18(9):1274-1284. 2. Pujade-Lauraine E et al. Presented at: SGO Annual Meeting; 2017.
196
99
89
14
104
17
118
18
134
22
156
37
182
70
82
12
32
7
29
6
2
0
0
0
Olaparib 300 mg BID tablets
Placebo BID
Investigator-Assessed PFS
Time from Randomisation (months)
1815129630 21 24 27 33
ProportionofPatientsProgressionFree
0.0
0.2
0.4
0.6
0.8
1.0
30
3
0
Olaparib 300 mg
BID tablets
Placebo
BID
Events, n (%) 107/196 (54.6) 80/99 (80.8)
Median PFS,
mo
19.1 5.5
HR=0.30
(95% CI, 0.22–0.41)
P<0.0001
Over their first two years of treatment, almost 70% of patients were able to remain on 300 mg BID tablets
38
SOLO-2: The Majority of Patients Remained on Starting Dose of
Olaparib (300 mg BID Tablets)
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Treatment Month
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
ProportionofPatients
195 190 189 182 175 169 156 153 147 139 134 129 122 121 115 110 108 104 101 100 97 94 92 77
Number of patients treated:
200 mg BID tablets
300 mg BID tablets
250 mg BID tablets
Other regimen*
No dosing**
Denominator for each month is the number of patients treated at the start of the month or after. Each patient is counted at the first non-missing dose level within the given month window.
*Included: 150 mg QD, 200 mg QD, 250 mg QD, 300 mg QD, 150 mg BID, 150 mg TID. **If the patient had dosing interrupted for the entire month window, the category of no dosing was assigned.
BID=twice daily; QD=once daily; TID=three times daily
Korach J et al. Presented at: ESMO Annual Meeting; 2018.
SOLO-2:
• There was no appreciable difference in quality of life for patients receiving olaparib (300 mg BID
tablets*) compared with those receiving placebo, as assessed with the TOI score derived from the
FACT-O questionnaire2
• Additional analyses of QAPFS and TWiST (Time Without Symptom or Toxicity) demonstrated a
significant improvement for patients in the olaparib treatment group (300 mg BID tablets*) compared
with placebo3
Study 19:
• There were no significant differences in disease-related symptoms or rates of improvement in HRQoL
with olaparib (400 mg BID capsules*) and placebo, as measured by scores on the FACT–O questionnaire,
NCCN-FACT Ovarian Symptom Index, and TOI1
Study 19 and SOLO-2: Health-Related Quality of Life (HRQoL)
*Olaparib capsules and tablets are not interchangeable.
BID=twice daily; FACT-O=Functional Assessment of Cancer Therapy-Ovarian Cancer; NCCN-FACT=National Comprehensive Cancer Network–FACT; QAPFS=quality-adjusted progression-free survival;
TOI=Trial Outcome Index; TWiST=time without symptoms of disease or toxicity.
1. Ledermann J et al. N Engl J Med. 2012;366:1382–1392. 2. Pujade-Lauraine E et al. Lancet Oncol. 2017;18(9):1274–1284. 3. Friedlander M et al. J Clin Oncol. 2017;35(suppl):5507.
Time from Randomisation (months)
Probability
1.0
0.8
0.6
0.4
0.2
0.0
0 3 6 9 12 15 18 21 24 27
Olaparib 300 mg
BID tablets
TWiST
Toxicity
Time from Randomisation (months)
1.0
0.8
0.6
0.4
0.2
0.0
0 3 6 9 12 15 18 21 24 27
Placebo BID
Probability
TWiST
Toxicity
Olaparib 300 mg
BID tablets, mo
n=185
Placebo BID, mo
n=94
Difference
(95% CI) P value
TWiST 13.5 7.21
6.29
(2.95–8.58)
<0.0001
Toxicity 3.69 0.71
2.98
(1.52–4.68)
0.0002
Bevacizumab Is Here in Frontline—What About PARPi?
Phase III PRIMA: NCT02655016
Niraparib maintenance for
newly diagnosed advanced OC
Niraparib4
Olaparib +
Bev3
Phase III PAOLA-1: NCT02477644
Olaparib + Bev maintenance for
newly diagnosed advanced OC
Phase III SOLO-1: NCT01844986
Olaparib maintenance for newly
diagnosed advanced BRCAm OCOlaparib1
Phase III GOG-3005: NCT02470585
PC +/- concurrent and maintenance veliparib
for newly diagnosed advanced OC
Bev=bevacizumab; BRCAm=BRCA mutated; OC=ovarian cancer; PARPi=PARP inhibitor; PC=paclitaxel and carboplatin.
1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01844986. Accessed 1 October 2018. 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02470585. Accessed 1
October 2018. 3. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02477644. Accessed 1 October 2018. 4. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02655016.
Accessed 1 October 2018.
Veliparib2
SOLO-1: PHASE III TRIAL OF MAINTENANCE OLAPARIB
FOLLOWING PLATINUM-BASED CHEMOTHERAPY IN
NEWLY DIAGNOSED PATIENTS WITH ADVANCED
OVARIAN CANCER AND A BRCA1/2 MUTATION
1Stephenson Oklahoma Cancer Center, Oklahoma City, OK, USA; 2University of Milan-Bicocca and IEO, European Institute of Oncology IRCCS, Milan, Italy; 3Fondazione Policlinico
Universitario A. Gemelli IRCCS Università Cattolica, Rome, Italy; 4Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 5Vall d'Hebron University
Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; 6University of New South Wales Clinical School, Prince of Wales Hospital, Randwick, Australia; 7St Petersburg
City Oncology Dispensary, St Petersburg, Russia; 8Institut Bergonié, Comprehensive Cancer Centre, Bordeaux, France; 9Gustave-Roussy Cancer Campus, Villejuif, France;
10The Netherlands Cancer Institute, Amsterdam, The Netherlands; 11Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh,
Edinburgh, UK; 12The Royal Marsden NHS Foundation Trust, London, UK; 13Princess Margaret Cancer Centre, Toronto, ON, Canada; 14MD Anderson Cancer Centre Madrid, Madrid,
Spain; 15Memorial Sloan Kettering Cancer Center, New York, NY, USA; 16Froedtert and the Medical College of Wisconsin, Milwaukee, WI, USA; 17AstraZeneca, Gaithersburg, MD, USA;
18AstraZeneca, Cambridge, UK; 19Women & Infants Hospital, Providence, RI, USA
Kathleen Moore,1 Nicoletta Colombo,2 Giovanni Scambia,3 Byoung-Gie Kim,4 Ana Oaknin,5
Michael Friedlander,6 Alla Lisyanskaya,7 Anne Floquet,8 Alexandra Leary,9 Gabe S. Sonke,10
Charlie Gourley,11 Susana Banerjee,12 Amit Oza,13 Antonio González-Martín,14 Carol Aghajanian,15
William Bradley,16 Elizabeth S. Lowe,17 Ralph Bloomfield,18 Paul DiSilvestro19
ClinicalTrials.gov identifier: NCT01844986. This study was sponsored by AstraZeneca; part of an alliance between AstraZeneca and Merck & Co., Inc.
SOLO-1: Study Design
Upfront or interval attempt at optimal cytoreductive surgery for stage III disease and either biopsy and/or upfront or interval cytoreductive surgery for stage IV disease.
BICR=blinded independent central review; BID=twice daily; ECOG=Eastern Cooperative Oncology Group; FACT-O=Functional Assessment of Cancer Therapy – Ovarian Cancer;
FIGO=International Federation of Gynecology and Obstetrics; HRQoL=health-related quality of life; PFS=progression-free survival; PFS2=time to second progression or death;
RECIST=Response Evaluation Criteria In Solid Tumours; TOI=Trial Outcome Index.
Moore K et al. Presented at: ESMO annual meeting; 2018.
• Newly diagnosed, FIGO
stage III–IV, high-grade serous
or endometrioid ovarian
cancer, primary peritoneal
cancer and/or fallopian tube
cancer
• Germline or somatic BRCAm
• ECOG performance status 0–1
• Cytoreductive surgery
• Completed platinum-based
chemotherapy
• In clinical complete response or
partial response
Primary endpoint
• Investigator-assessed PFS
(modified RECIST 1.1)
Secondary endpoints
• PFS using BICR
• PFS2
• Overall survival
• Time from randomisation to first
subsequent therapy or death
• Time from randomisation to
second subsequent therapy or
death
• HRQoL (FACT-O TOI score)
Olaparib 300 mg BID
(n=260)
Placebo
(n=131)
• Study treatment continued
until disease progression
• Patients with no evidence
of disease at 2 years
stopped treatment
• Patients with a partial
response at 2 years could
continue treatment
2:1 randomisation
Stratified by response to
platinum-based
chemotherapy
Olaparib
(n=260)
Placebo
(n=131)
Events (%) 102 (39.2) 96 (73.3)
Median
PFS, mo
NR 13.8
HR=0.30
95% CI, 0.23–0.41
P<0.0001
SOLO-1: PFS by Investigator Assessment (50.6% Maturity)
CI=confidence interval; NR=not reached; HR=hazard ratio; PFS=progression-free survival.
Moore K et al. Presented at: ESMO annual meeting; 2018.
0 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
0
10
20
30
40
50
60
70
80
90
100
3
Investigator-Assessed
Progression-FreeSurvival(%)
Time from Randomisation (months)
260
131
229
103
221
82
212
65
201
56
194
53
184
47
172
41
149
39
138
38
133
31
111
28
88
22
45
6
36
5
4
1
3
0
0
0
0
0
0
0
240
118
No. at risk
Olaparib
Placebo
Olaparib
Placebo
SOLO-1: PFS Landmark Analysis
87.7
51.4
73.6
34.6
60.4
26.9
52.6
11.4
Based on Kaplan-Meier estimates, after 3 years, 60.4% of patients in the olaparib arm were
progression-free compared with 26.9% of patients in the placebo arm
12 months
0
10
20
30
40
50
60
70
80
90
100
FreeofProgressionorDeath(%)
24 months 36 months 48 months
Olaparib Placebo
PFS=progression-free survival.
Moore K et al. Presented at: ESMO annual meeting; 2018.
11.5
26.9
3.8
19.2
24.6
10
14.6
41.5
37.7
23.1
25.4
26.2
27.7
34.2
38.8
40.0
63.5
77.3
SOLO-1: Most Common Treatment-Emergent Adverse Events
Olaparib (n=260) Placebo (n=130)
Adverse events (%)
Constipation
Dysgeusia
Neutropenia*
Nausea
Fatigue/asthenia*
Vomiting
Diarrhoea
Arthralgia
Anaemia*
0.8
3.8
0.4
21.5
3.1
8.5 4.6
1.5
0.8
1.5
All grades (frequency ≥25%)
Grade ≥3 (frequency ≥5%)
All grades (frequency ≥25%)
Grade ≥3 (frequency ≥5%)
*Grouped terms. All-grade thrombocytopenia (grouped term) occurred in 11.2% of patients in the olaparib group and 3.8% of patients in the placebo group and grade ≥3
thrombocytopenia (grouped term) occurred in 0.8% and 1.5%, respectively.
Moore K et al. Presented at: ESMO annual meeting; 2018.
100 75 50 25 0 0 25 50 75 100
Ongoing Frontline Trials With PARPi
*Includes patients with primary peritoneal and/or fallopian tube cancer.
†Tablet formulation (2 tablets twice daily).
ECOG=Eastern Cooperative Oncology Group; FIGO=International Federation of Gynecology and Obstetrics; gBRCAm=germline BRCA mutation; HRQoL=health-related quality of life; OS=overall
survival; PFS1=time to first progression; PFS2=time to second progression; PRO=patient-reported outcome; PS=performance status; RECIST=Response Evaluation Criteria In Solid Tumours; TSST=time
to second subsequent therapy.
ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02470585. Accessed 1 October 2018.
VELIA: Phase 3 Trial of Veliparib With Carboplatin and Paclitaxel
as Continuous Maintenance
FIGO stage III–IV high-grade
ovarian cancer (serous)* or
non-mucinous BRCAm
ECOG PS 0–1
gBRCA testing
prior to
randomisation
Randomise 1:1
N≈1140
Primary endpoint
• PFS1 (RECIST 1.1)
Secondary endpoints
• PFS2
• TSST
• OS
• Safety
• PRO/HRQoL
Veliparib + Carboplatin
and Paclitaxel → Veliparib
maintenance
Placebo
Carboplatin and
Paclitaxel → Placebo
maintenance
Stratify by:
• BRCA status
Status: Completed enrolment
PAOLA-1: Phase 3 Trial of Olaparib vs Placebo Plus Bevacizumab as
Maintenance Treatment in Patients With Advanced Ovarian Cancer
FIGO stage III–IV high-
grade ovarian cancer
(serous or endometrioid)*
or non-mucinous BRCAm
No evidence of disease or
CR or PR following
first-line platinum-based
chemotherapy plus
bevacizumab
A minimum of 3 cycles of
platinum-based
chemotherapy plus
bevacizumab (2 after
interval debulking)
ECOG PS 0–1
BRCA testing
prior to
randomisation
Randomise 2:1
N≈806 European +
24 Japanese patients
Primary endpoint
• PFS1 (RECIST 1.1)
Secondary endpoints
• PFS2
• TSST
• OS
• Safety
• PRO/HRQoL
Olaparib
300 mg† PO BID +
bevacizumab
15 mg/kg Q3W
15 months
Placebo +
bevacizumab
15 mg/kg Q3W
15 months
Stratify by:
• tBRCA status
• CR/PR/NED
Status: Completed enrolment
*Includes patients with primary peritoneal and/or fallopian tube cancer. †Tablet formulation (2 tablets twice daily).
BID=twice daily; BRCAm=BRCA mutation; CR=complete response; ECOG=Eastern Cooperative Oncology Group; FIGO=International Federation of Gynecology and Obstetrics; HRQoL=health-related
quality of life; NED=no evidence of disease; OS=overall survival; PFS1=time to first progression; PFS2=time to second progression; PO=by mouth; PR=partial response; PRO=patient-reported outcome;
PS=performance status; Q3W=every 3 weeks; RECIST=Response Evaluation Criteria In Solid Tumours; tBRCA=tumour BRCA; TSST=time to second subsequent therapy.
1. Ray-Coquard IL et al. J Clin Oncol. 2017;35(15_suppl). 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02477644. Accessed 1 October 2018.
• Study treatment continued
until disease progression
• Patients with no evidence
of disease at 2 years
stopped treatment
• Patients with a partial
response at 2 years could
continue treatment
*Includes patients with primary peritoneal and/or fallopian tube cancer.
†Tablet formulation (2 tablets twice daily).
BRCAm=BRCA mutation; CR=complete response; ECOG=Eastern Cooperative Oncology Group; FIGO=International Federation of Gynecology and Obstetrics; HRD=homologous recombination
deficiency; HRQoL=health-related quality of life; NED=no evidence of disease; OS=overall survival; PFS1=time to first progression; PFS2=time to second progression; PO=by mouth; PR=partial
response; PRO=patient-reported outcome; PS=performance status; Q3W=every 3 weeks; QD=once daily; RECIST=Response Evaluation Criteria In Solid Tumours; TSST=time to second subsequent
therapy.
ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02655016. Accessed 1 October 2018
PRIMA: Phase 3 Trial of Niraparib vs Placebo as Maintenance
Treatment in Patients With Advanced Ovarian Cancer
FIGO stage III–IV high-grade
ovarian cancer (serous or
endometrioid)* or
non-mucinous BRCAm
CR or PR following first-line
platinum-based chemotherapy
Stage IV patients are eligible,
irrespective of residual
disease. Stage III patients are
required to have visible
residual disease after primary
surgery
HRD testing prior
to randomisation
Randomise 2:1
N≈620
Primary endpoint
• PFS1 (RECIST 1.1)
Secondary endpoints
• PFS2
• TSST
• OS
• Safety
• PRO/HRQoL
Niraparib
300 mg† PO QD
PlaceboStratify by:
• HRD status
• CR/PR/NED
Status: Completed enrolment
Overview of Studies Evaluating PARPi in
Frontline Maintenance
SOLO-11,2 PAOLA-13,4 PRIMA5
Key Inclusion Criteria Germline or somatic BRCAm Regardless of BRCAm
Regardless of BRCAm;
Stage III patients are required to
have visible residual disease
after surgery
Treatment Arms Olaparib vs placebo
Olaparib + bevacizumab vs
placebo + bevacizumab
Niraparib vs placebo
Prior Treatment
NED/CR/PR following first-line
platinum-based chemotherapy
NED/CR/PR following first-line
platinum-based chemotherapy
+ bevacizumab
CR/PR following first-line
platinum-based chemotherapy
Treatment Duration 24 months*
Bevacizumab for 15 months and
olaparib for 24 months*
Until disease progression
Current Status of Trial Primary endpoint met Enrolment complete Enrolment complete
*Or until disease progression.
BRCAm=BRCA mutation; CR=complete response; NED=no evidence of disease; PR=partial response.
1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01844986. Accessed 1 October 2018. 2. AstraZeneca Press Release. https://www.astrazeneca.com/media-centre/press-
releases/2018/lynparza-significantly-delays-disease-progression-in-phase-iii-1st-line-solo-1-trial-for-ovarian-cancer.html. Accessed 3 October 2018. 3. Ray-Coquard IL et al. J Clin Oncol.
2017;35(15_suppl). 4. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02477644. Accessed 1 October 2018. 5. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02655016.
Accessed 1 October 2018.
Bevacizumab and PARPi Are Here in Frontline—
What About Immunotherapy?
Bev=bevacizumab; BRCAm=BRCA mutated; OC=ovarian cancer; PARPi=PARP inhibitor; PC=paclitaxel and carboplatin.
1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01844986. Accessed 1 October 2018. 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02470585 . Accessed 1
October 2018. 3. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02477644. Accessed 1 October 2018. 4. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02655016.
Accessed 1 October 2018.
Phase III PRIMA: NCT02655016
Niraparib maintenance for
newly diagnosed advanced OCNiraparib4
Olaparib +
Bev3
Phase III PAOLA-1: NCT02477644
Olaparib + Bev maintenance for
newly diagnosed advanced OC
Phase III SOLO-1: NCT01844986
Olaparib maintenance for newly
diagnosed advanced BRCAm OCOlaparib1
Phase III GOG-3005: NCT02470585
PC +/- concurrent and maintenance veliparib
for newly diagnosed advanced OC
Veliparib2
What’s
next?
The Rationale for Targeting PD-L1 in Ovarian Cancer
OC is associated with
mutational burden1
Tumour mutations
increase tumour-specific
antigens2
>50% of OC tumours show
tumour-infiltrating T cells
at diagnosis3
Improved OC
outcomes?
Immunosuppressive
tumour
microenvironment
Anti-PDL1 or
anti-PD1
OC=ovarian cancer; PD-1=programmed death-1; PD-L1=programmed death-ligand 1.
1. Lawrence MS et al. Nature. 2013;499(7457):214-218. 2. Strickland K et al. J Clin Oncol. 2015;33(15_suppl):5512. 3. Zhang L et al. N Engl J Med. 2003;348(3):203-213. 4. Hamanishi J et al.
Proc Natl Acad Sci. 2007;104(9):3360-3365. 5. Abiko K et al. Clin Cancer Res. 2013;19(6):1363-1374.
Increased expression of
immune checkpoint
modulators
(PD-L1 and PD-1)4,5 as a
potential mechanism of
resistance
Immunotherapies Are Coming Soon—What About
in Combination With PARPi?
Phase III PRIMA: NCT02655016
Niraparib maintenance for
newly diagnosed advanced OCNiraparib4
Olaparib +
Bev3
Phase III PAOLA-1: NCT02477644
Olaparib + Bev maintenance for
newly diagnosed advanced OC
Phase III SOLO-1: NCT01844986
Olaparib maintenance for newly
diagnosed advanced BRCAm OCOlaparib1
Phase III GOG-3005: NCT02470585
PC +/- concurrent and maintenance veliparib
for newly diagnosed advanced OC
Bev=bevacizumab; BRCAm=BRCA mutated; IO=immuno-oncology; OC=ovarian cancer; PARPi=PARP inhibitor; PC=paclitaxel and carboplatin.
1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01844986. Accessed 1 October 2018. 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02470585. Accessed 1
October 2018. 3. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02477644. Accessed 1 October 2018. 4. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02655016.
Accessed 1 October 2018. 5. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02718417. Accessed 2 October 2018. 6. ClinicalTrials.gov.
https://clinicaltrials.gov/ct2/show/NCT03038100. Accessed 11 October 2018.
Veliparib2
Javelin 1005
Phase III JAVELIN OVARIAN-100: NCT02718417
Avelumab in combo with and/or following
chemo for newly diagnosed advanced OC
IMagyn0506
Phase III IMagyn050: NCT03038100
Chemo + Bev +/- atezolizumab for
newly diagnosed advanced OC
What about
IO + PARPi?
Block immunosuppression
within the tumour microenvironment and
enhance tumour cell death3
Anti-PDL1
Anti-PD1
Increase T-cell trafficking and infiltration into tumours1
Anti-VEGF
Combination Opportunities in Ovarian Cancer:
Immunotherapy and PARP Inhibition
Enhance antigen presentation
and T-cell activation2
Chemotherapy
Radiotherapy
PARPi
RECRUIT/
INFILTRATE
(vasculature)
Non-inflamed
ACTIVATE
(central)
Non-inflamed
KILL
CANCER CELLS
(tumour) inflamed
PARPi=PARP inhibitor; PD-1=programmed death-1; PD-L1=programmed death-ligand 1; VEGF=vascular endothelial growth factor.
1. Vanneman M et al. Nat Rev Cancer. 2012;12(4):237-251. 2. Brown JS. Br J Cancer. 2018;118(3):312-324. 3. Chen DS et al. Immunity. 2013;39(1):1-10.
PARPi
• Enhanced DNA damage
and mutational load in
tumour cells
Overview of Ongoing Phase 3 Trials With Immunotherapy + PARPi
for the Treatment of Ovarian Cancer
ENGOT-ov44/ FIRST1 Javelin Ovarian 100
PARP2 ATHENA3 ENGOT-ov46/
DUO-O4
Patient Population
Newly diagnosed advanced
ovarian cancer
Newly diagnosed advanced
ovarian cancer
Newly diagnosed advanced
ovarian cancer
Newly diagnosed advanced
ovarian cancer
Treatment Arms
• Platinum + TSR-042
(PD-L1i) followed by niraparib
+ TSR-042
• Adaptive standard
platinum-based treatment
• Avelumab + chemo followed
by avelumab + talazoparib
• Chemo followed by
talazoparib
• Chemo + Bev followed by Bev
• Rucaparib + nivolumab
• Rucaparib + IV placebo
• Nivolumab + oral placebo
• Oral placebo + IV placebo
• Chemo + durvalumab +/-
bevacizumab followed by
durvalumab + bevacizumab +
olaparib
Prior Treatment None None Platinum-based chemotherapy None
Expected Primary
Completion Date
June 2020 February 2022 December 2024 —
Bev=bevacizumab; IV=intravenous; PARPi=PARP inhibitor; PD-L1i=programmed death-ligand 1 inhibitor.
1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03602859. Accessed 19 October 2018. 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03642132. Accessed 2 October
2018. 3. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03522246. Accessed 3 October 2018. 4. ENGOT Ovarian Cancer Clinical Trials. https://engot.esgo.org/clinical-
trials/current-clinical-trials/ovarian/. Accessed 3 October 2018.
✓ Most include active agent in combination with carboplatin-paclitaxel
✓ ATHENA is switch maintenance only IO study
✓ Three virtually identical studies (FIRST, ENGOT-ov43, ENGOT-ov46/DUO-O)
✓ Others incorporate active agents in both treatment and as maintenance (continuous or switch)
The Frontline Ovarian Cancer Space Is a Crowded Landscape!
First-Line Treatment
with Maintenance
First-Line Switch Maintenance
First-Line Treatment/
Maintenance with IO
First-Line Treatment/
Maintenance with IO and PARPi
GOG 218 SOLO-1 FIRST FIRST
Javelin Ovarian 100 PAOLA-1 ENGOT-ov43 ENGOT-ov43
Javelin Ovarian 100 PARP PRIMA ENGOT-ov46/DUO-O ENGOT-ov46/DUO-O
VELIA 3005 ATHENA ATHENA ATHENA
IMagyn50 3015 Javelin Ovarian 100 Javelin Ovarian 100 PARP
FIRST Javelin Ovarian 100 PARP
ENGOT-ov43 IMagyn50 3015
ENGOT-ov46/DUO-O
IO=immuno-oncology; PARPi=PARP inhibitor.
Slide courtesy of Brad Monk, MD.
What’s the Status of Frontline Trials?
Planned Actively Enrolling Closed—Results Pending Completed
FIRST ATHENA VELIA 3005 GOG218
ENGOT-ov43 IMagyn050 3015 PAOLA-1 ICON7
ENGOT-ov46/DUO-O JAVELIN Ovarian 100 PARP PRIMA SOLO-1
Javelin Ovarian 100
JAVELIN 200 (Recurrent)
FORWARD- 1 (Recurrent)
Slide courtesy of Brad Monk, MD.
Frontline treatment is becoming more challenging
• Bevacizumab is here—is it for everyone?
• Olaparib is here for BRCAm (SOLO-1)
• Olaparib + bevacizumab trial ongoing (PAOLA-1)
• Niraparib trial ongoing (PRIMA)
Frontline treatment choices may impact decision-making in second-line/platinum-sensitive setting
• Looks like we can re-use bevacizumab
• If you received PARPi in front line—can you re-use? In what circumstance?
– OrEO trial ongoing to assess rechallenging with PARPi
• How does immunotherapy fit into the relapsed setting if used in frontline?
Conclusions
BRCAm=BRCA mutated; PARPi=PARP inhibitor.

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The Changing Role of PARP Inhibitors in the Treatment of Ovarian Cancer

  • 1. PIVOTAL TRIALS IN OVARIAN CANCER: WHAT HAS DEFINED THE STANDARD OF CARE TO DATE?
  • 2. The Typical Course of Advanced Ovarian Cancer1-5 *Around 5% of patients are primary treatment-refractory, meaning disease progressed during therapy or within 4 weeks after the last dose. IDS=interval debulking surgery. 1. Ledermann JA et al. Ann Oncol. 2013;24(Suppl 6):vi24-vi32. 2. Giornelli GH. Springerplus. 2016;5(1):1197. 3. Pignata S et al. Ann Oncol. 2017;28(suppl_8):viii51-viii56. 4. du Bois A et al. Cancer. 2009;115(6):1234-1244. 5. Wilson MK et al. Ann Oncol. 2017;28(4):727-732. First-Line Treatment Stage III, IV First Response* Surgery (primary or IDS) + primary or adjuvant chemotherapy +/- bevacizumab Second Response/ Disease Stabilisation Patients for whom platinum is an option, formerly ‘Platinum-Sensitive’ Progression >6 months after completion of platinum-based chemotherapy Patients for whom platinum is not an option, formerly ‘Platinum-Resistant’ Progression <6 months after completion of platinum-based chemotherapy Relapse/ Progression (100%) Relapse/ Progression (70%–80%) Follow-up
  • 3. Ovarian Cancer: Course of Disease AGO=Arbeitsgemeinschaft Gynäkologische Onkologie; FIGO=International Federation of Gynecology and Obstetrics; PFS=progression-free survival. 1. du Bois A et al. Cancer. 2009;115(6):1234-1244. 2. Data from the AGO Study Group. Adapted from a slide curtesy of Prof Frederik Marmé. Time (months) Progression-FreeSurvival (3126patients/275events)(%) 21.8% relapse 0-6 months after chemotherapy (resistant) 22.5% relapse within 6-12 months after chemotherapy (partially sensitive) 0 120108 1322412 48 72 84 9636 60 100 0 70 50 30 10 90 60 40 20 80 31.6% relapse within 12-60 months after chemotherapy (sensitive) Primary resistance Secondary resistance Cure Median PFS 18.2 months 21.8% relapse within 6 months 54.1% relapse after > 6 months 31.6% after > 12 months 24% never relapse FIGO IIB-IV: Individual patient data meta-analysis of three AGO phase 3 first-line trials (AGO Ovar 3, 5, 7)1,2 5 year PFS 22.6%
  • 4. Ovarian Cancer Is Not One Disease, Yet All Types are Treated the Same Banerjee S et al. Clin Cancer Res. 2013;19(5):961-968. Ovarian cancer Epithelial Nonepithelial High-grade serous Low-grade serous Mucinous Clear cell Endometrioid Sex cord-stromal Others, including germ cell TP53 BRCA1 and 2 NF1 RB1 CDK12 Homologous recombination repair genes BRAF KRAS NRAS ERBB2 KRAS HER2 amplification ARID1A PIK3CA PTEN CTNNB1 PPP2R1α ARID1A PIK3CA PTEN PPP2R1α MMR deficiency Granulosa cell FOXL2 Sertoll-Leydig cell DICER1 Pathway alterations: PI3K/RAS/NOTCH/FOXM1 Paclitaxel and carboplatin Nonepithelial Sex cord-stromal Others, including germ cell Granulosa cell FOXL2 Sertoli-Leydig cell DICER1
  • 5. First-Line Surgical Cytoreduction • To date, 3 trials (EORTC 55971, CHORUS, JCOG0602) comparing primary chemotherapy with interval debulking surgery (NACT) and primary debulking surgery followed by chemotherapy have shown no differences in PFS/OS3-5 – NB. Rate of no residual disease was relatively low in these studies – Are there selected patients for whom one approach is preferable/better? • TRUST trial ongoing to address role of radical surgery6 CI=confidence interval; HR=hazard ratio; NACT=neoadjuvant chemotherapy; NB=nota bene; OS=overall survival; PFS=progression-free survival. 1. du Bois A et al. Cancer. 2009;115(6):1234-1244. 2. Harter P et al. J Clin Oncol. 2017;35(15_suppl):5500. 3. Vergote I et al. N Engl J Med. 2010;363(10):943-953. 4. Kehoe S et al. Lancet. 2015;386(9990):249-257. 5. Onda T et al. Eur J Cancer. 2016;64:22-31. 6. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02828618. Accessed 25 September 2018. HR (95% CI) 1-10 mm vs 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1-10 mm: 1.36 (1.24; 1.50) Log-rank P<0.0001 100 75 50 25 0 0 12 24 36 48 60 72 84 96 108 120 132 144 OverallSurvival(%) 0 mm 1-10 mm >10 mm • Surgical cytoreduction is the strongest stage-related independent prognostic factor1 • Aim for no residual disease1 • Lymphadenectomy of non-enlarged lymph nodes in patients with advanced ovarian cancer and complete resection should be omitted2 Overall Survival1 Time (months)
  • 6. First-Line Systemic Neoadjuvant Chemotherapy (NACT) Wright AA et al. J Clin Oncol. 2016;34(28):3460-3473. Surgery after 3-4 cycles recommended
  • 7. Weekly dose-dense chemotherapy can be delivered successfully as first-line epithelial ovarian cancer treatment without substantial toxicity increase; it does not significantly improve PFS compared to standard 3-weekly chemotherapy ICON8 Progression-Free Survival First-Line Chemotherapy Standard of Care: Carboplatin and Paclitaxel CI=confidence interval; HR=hazard ratio; PFS=progression-free survival. Clamp AR et al. Presented at: ESMO Annual Meeting; 2017. Standard (n=522) Weekly paclitaxel (n=523) Weekly carbo-paclitaxel (n=521) Progressions 330 (63%) 335 (64%) 338 (65%) Median PFS, mo 17.9 20.6 21.1 Log rank (vs standard) P=0.45 P=0.56 HR vs Standard (97.5% CI) 0.92 (0.77–1.09) 0.94 (0.79–1.12) Restricted means 24.4 months 24.9 months 25.3 months 522 318 1354471 198 92 59 32250 130Standard No. at risk 523 17383489 210 92 59 28279 144Weekly paclitaxel 3 0 521 15385468 208 99 66 33281 153Weekly carbo-paclitaxel 6 0 Time from Randomisation (months) 0 6054 66126 24 36 42 4818 30 1.00 0.00 0.50 0.25 0.75 Standard Weekly paclitaxel Weekly carbo-paclitaxel Progression-FreeSurvival(proportion)
  • 8. First-Line Bevacizumab: Progression-Free Survival Bev=bevacizumab. 1. Burger RA et al. N Engl J Med. 2011;365(26):2473-2483. 2. Perren TJ et al. N Engl J Med. 2011;365(26):2484-2496. GOG 2181 625 8199 33Chemotherapy 625 6219 29Bev initiation 623 8254 38Bev throughout ICON72 No. at risk 764 25693 216Chemotherapy 464 91 764 19715 263Bevacizumab 585 73 No. at risk 100 0 0 30 Progression-FreeSurvival(%) Time from Randomisation (months) Bevacizumab Chemotherapy 19.0 months 17.3 months 3 6 9 12 15 18 21 24 27 75 50 25 Time from Randomisation (months) 1.0 0.6 0.4 0.0 0 2 14 22 28 36 Progression-FreeSurvival (proportion) 0.2 0.8 0.9 0.7 0.5 0.3 0.1 4 6 8 10 12 16 18 20 24 26 30 32 34 Bev initiation Bev throughout Chemotherapy 14.1 months 10.3 months Advanced epithelial ovarian cancer Paclitaxel + carboplatin + placebo Placebo Placebo (Bev Initiation) Bevacizumab (Bev throughout) Paclitaxel + carboplatin + bevacizumab Cycles 1–6; + bevacizumab at cycle 2 Until disease progression or up to 22 cycles Advanced epithelial ovarian cancer Paclitaxel + carboplatin Bevacizumab Paclitaxel + carboplatin + bevacizumab Cycles 1–6 Until disease progression or 12 cycles
  • 9. First-Line Bevacizumab: Overall Survival No overall survival benefit was demonstrated;1,2 bevacizumab was approved by the EMA and FDA for first-line treatment in December 2011 and June 2018, respectively4,5 Bev=bevacizumab; CI=confidence interval; EMA=European Medicines Agency; FDA=US Food and Drug Administration; HR=hazard ratio. 1. Burger RA et al. N Engl J Med. 2011;365(26):2473-2483. 2. Perren TJ et al. N Engl J Med. 2012;365(26):2484-2496. 3. Oza AM et al. Lancet Oncol. 2015;16(8):928-936. 4. Roche Media Release. https://www.roche.com/dam/jcr:47093e15-51d4-47ca-9bbb-a082d7bf0dd1/en/med-cor-2011-12-23-e.pdf. Accessed 5 October 2018. 5. Roche Media Release. https://www.roche.com/dam/jcr:01d38b33-167d-46a6-87f9-4e5f3f0340d3/en/20180613-MR-Avastin_FDA_en.pdf. Accessed 5 October 2018. GOG 2181 1.0 0.8 0.6 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 Time from Randomisation (months) OverallSurvival(proportion) 625 442 173 46Chemotherapy No. at risk 625 432 162 39Bev initiation 623 437 171 40Bev throughout Chemotherapy Bevacizumab initiation Bevacizumab throughout 156 (25.0) 150 (24.0) 138 (22.2) No. of events (%) ICON72 100 75 50 25 0 0 3 6 12 21 30 Time from Randomisation (months) OverallSurvival(%) 272418159 No. at risk 764Standard chemotherapy 724 652 33159368 764Bevacizumab 737 678 40162404 Standard chemotherapy Bevacizumab ICON7 subgroup, high risk: residual disease >1 cm/Stage IV ICON73 1.00 0.75 0.50 0.25 0 0 6 12 24 42 60 Time from Randomisation (months) OverallSurvival(proportion) 5448363018 Standard chemotherapy Bevacizumab High risk: HR=0.78 (95% CI, 0.63–0.97) 66% events Non-high risk: HR=1.14 (95% CI, 0.93–1.40) 37% events Interaction: P=0.01
  • 10. Need to improve QoL, PFS, TFST, TSST, OS, and the cure rate Delay the psychological burden of disease progression Delay the physical symptoms associated with progressive disease The Need Surgery (primary or IDS) with carboplatin and paclitaxel (+/- bevacizumab) is the current standard of care Intraperitoneal, HIPEC remains an area for further studies The Current Standard Factors to consider: age, performance status, comorbidities, extent of surgery, histology, molecular markers (eg, BRCA, HRD) Other Factors Unmet Needs for Patients With Newly-Diagnosed Ovarian Cancer There is a need for additional safe and effective maintenance options following completion of first-line surgery and chemotherapy to improve patient outcomes HIPEC=hyperthermic intraperitoneal chemotherapy; HRD=homologous recombination deficiency; IDS=interval debulking surgery; OS=overall survival; PFS=progression-free survival; QoL=quality of life; TFST=time to first subsequent therapy or death; TSST=time to second subsequent therapy or death.
  • 11. The Typical Course of Advanced Ovarian Cancer1-5 *Around 5% of patients are primary treatment-refractory, meaning disease progressed during therapy or within 4 weeks after the last dose. IDS=interval debulking surgery. 1. Ledermann JA et al. Ann Oncol. 2013;24(Suppl 6):vi24-vi32. 2. Giornelli GH. Springerplus. 2016;5(1):1197. 3. Pignata S et al. Ann Oncol. 2017;28(suppl_8):viii51-viii56. 4. du Bois A et al. Cancer. 2009;115(6):1234-1244. 5. Wilson MK et al. Ann Oncol. 2017;28(4):727-732. First-Line Treatment Stage III, IV First Response* Surgery (primary or IDS) + primary or adjuvant chemotherapy +/- bevacizumab Follow-up Second Response/ Disease Stabilisation Patients for whom platinum is an option, formerly ‘Platinum-Sensitive’ Progression >6 months after completion of platinum-based chemotherapy Patients for whom platinum is not an option, formerly ‘Platinum-Resistant’ Progression <6 months after completion of platinum-based chemotherapy Relapse/ Progression (100%) Relapse/ Progression (70%–80%)
  • 12. An Example of the Course of Advanced Ovarian Cancer for an Individual Patient CA–125level FIRST LINE: surgery, carboplatin + paclitaxel +/- bevacizumab FIFTH LINE: carboplatin + gemcitabine Bowel obstruction Death SECOND LINE: carboplatin + PLD followed by PARPi THIRD LINE: weekly paclitaxel FOURTH LINE: clinical trial Symptoms PFS PFS PFS PFS PFS Time PARPi=PARP inhibitor; PFS=progression-free survival; PLD=pegylated liposomal doxorubicin. Ledermann JA et al. Ann Oncol. 2013;24(Suppl 6):vi24-vi32.
  • 13. Treatment Options for Patients With Relapsed Ovarian Cancer for Whom Platinum is an Option
  • 14. Combination vs Single-Agent Platinum Chemotherapy for Patients With Relapsed Ovarian Cancer for Whom Platinum is an Option Combination platinum chemotherapy improves OS and PFS compared with single-agent platinum chemotherapy CI=confidence interval; HR=hazard ratio; IV=instrumental variables; OS=overall survival; PFS=progression-free survival. Raja FA et al. Ann Oncol. 2013;24(12):3028-3034. Study Weight Hazard Ratio IV, Random, (95% CI) Hazard Ratio IV, Random, 95% CI ICON and AGO 2003 44.8% 0.81 (0.69–0.97) Pfisterer et al 2006 35.1% 0.96 (0.75–1.23) Alberts et al 2007 12.7% 0.69 (0.39–1.21) González-Mart. et al 2005 7.5% 0.39 (0.18–0.84) Total (95% CI) 100.0% 0.80 (0.64–1.00) Heterogeneity: Tau2=0.02; Chi2=5.44, df=3 (P=0.14); I2=45% Test of overall effect: Z=1.96 (P=0.05) Study Weight Hazard Ratio IV, Random, (95% CI) Hazard Ratio IV, Random, 95% CI ICON and AGO 2003 46.9% 0.75 (0.65–0.87) Pfisterer et al 2006 33.7% 0.72 (0.58–0.90) Alberts et al 2007 9.6% 0.52 (0.31–0.88) González-Mart. et al 2005 9.8% 0.45 (0.27–0.76) Total (95% CI) 100.0% 0.68 (0.57–0.81) Heterogeneity: Tau2=0.01; Chi2=4.70, df=3 (P=0.19); I2=36% Test of overall effect: Z=4.30 (P<0.0001) OverallSurvival Progression-Free Survival 0.1 0.2 0.5 1 2 5 10 Favors combination Favors single agent 0.1 0.2 0.5 1 2 5 10 Favors combination Favors single agent HR=0.8 HR=0.68
  • 15. Combinations for Patients With Relapsed Ovarian Cancer for Whom Platinum is an Option Trial Regimen Median PFS (months) Median OS (months) ICON41 Platinum chemotherapy/paclitaxel 12.0 29.0 CALYPSO2,3 Carboplatin/paclitaxel 9.4 33.0 CALYPSO2,3 Carboplatin/PLD 11.3 30.7 OVA-3014 Trabectedin/PLD 7.3 20.5* OVAR 2.55 Carboplatin/gemcitabine 8.6 18.0 OCEANS (control)6 Carboplatin/gemcitabine 8.4 35.2† OCEANS-bevacizumab6 Carboplatin/gemcitabine/bevacizumab 12.4 33.3† GOG 2137 Carboplatin/paclitaxel/bevacizumab 13.8 42.2 *Based on an interim analysis. †These data remain immature, with a high degree of censoring beyond month 18 and a longer-than-expected median OS in both arms. OS=overall survival; PFS=progression-free survival; PLD=pegylated liposomal doxorubicin. 1. Parmar MK et al. Lancet. 2003;361(9375):2099-2106. 2. Pujade-Lauraine E et al. J Clin Oncol. 2010;28(20):3323-3329. 3. Wagner U et al. Br J Cancer. 2012;107(4):588-591. 4. Monk BJ et al. J Clin Oncol. 2010;28(19):3107-3114. 5. Pfisterer J et al. J Clin Oncol. 2006;24(29):4699-4707. 6. Aghajanian C et al. J Clin Oncol. 2012;30(17):2039-2045. 7. Coleman RL et al. Lancet Oncol. 2017;18(6):779-791.
  • 16. Chemotherapy + Bev Bevacizumab for Patients With Relapsed Ovarian Cancer for Whom Platinum is an Option 2 positive trials: improvement in progression-free survival, first platinum-sensitive relapse Bevacizumab is administered in combination with either carboplatin and gemcitabine for 6 cycles and up to 10 cycles or in combination with carboplatin and paclitaxel for 6 cycles and up to 8 cycles, followed by continued use of bevacizumab as a single agent until disease progression3 Carboplatin + Gemcitabine +/- Bevacizumab Carboplatin + Paclitaxel +/- Bevacizumab GOG 213: PFS2 GOG213: OS2 HR=0.628; P<0.0001 HR=0.829; P<0.0056HR=0.48; P<0.0001 Progression-freesurvival(%) Time from Randomisation (months)No. at risk (number censored) Chemotherapy Chemotherapy + Bev 337 (0) 125 (15) 40 (16) 20 (17) 12 (23) 5 (28) 337 (0) 201 (7) 84 (7) 46 (10) 16 (27) 9 (32) Progression-freesurvival (proportion) 100 80 60 40 20 0 0 12 24 36 48 60 100 80 60 40 20 0 12 24 36 48 600 Overallsurvival(%) Time from Randomisation (months) No. at risk (number censored) Chemotherapy Chemotherapy + Bev 337 (0) 303 (15) 234 (17) 152 (30) 69 (77) 18 (109) 337 (0) 306 (8) 253 (9) 183 (20) 75 (82) 28 (110) Chemotherapy Chemotherapy + Bev The recommended dose of bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion. Bev=bevacizumab; HR=hazard ratio; OS=overall survival; PFS=progression-free survival. 1. Aghajanian C et al. J Clin Oncol. 2012;30(17):2039-2045. 2. Coleman RL et al. Lancet Oncol. 2017;18(6):779-791. 3. Avastin (Summary of Product Characteristics). Roche; 2018. OCEANS: PFS1 Chemotherapy Chemotherapy + Bev 1.0 Time from Randomisation (months) No. at risk Chemotherapy Chemotherapy + Bev 0.8 0.6 0.4 0.2 0 6 12 18 24 30 242 177 45 11 3 0 242 203 92 33 11 0 Chemotherapy Carboplatin + Paclitaxel +/- Bevacizumab
  • 17. Treatment Options for Patients With Relapsed Ovarian Cancer for Whom Platinum is Not an Option
  • 18. • Weekly paclitaxel (+/- bevacizumab) • Pegylated liposomal doxorubicin (PLD) (+/- bevacizumab) • Carboplatin and gemcitabine,* gemcitabine alone • Weekly carboplatin/paclitaxel • Topotecan (+/- bevacizumab) • Hormonal therapy (aromatase inhibitors, tamoxifen) • Metronomic cyclophosphamide • Olaparib (BRCA-mutated, 3 or more prior lines) Non-Trial Options for Patients With Relapsed Ovarian Cancer for Whom Platinum Is Not an Option *Consider carboplatin rechallenge in platinum-resistant disease depending on platinum-free interval. These select treatment options represent the speaker’s personal approach to treating patients with relapsed ovarian cancer for whom platinum is not an option.
  • 19. AURELIA: Practice Changing Trial ≤2 prior lines, Exclusion: platinum-refractory, prior (sub)obstruction, or bowel involvement N=360, randomised 1:1 Bevacizumab for Patients With Relapsed Ovarian Cancer for Whom Platinum Is Not an Option Improved PFS by adding bevacizumab to non-platinum based chemo + QoL benefit in symptomatic patients 60 50 40 30 0 Substantial Symptoms at Baseline Patientswith ≥15%Improvement(%) 20 10 Ascites at Baseline 12.7 29.6 44.0 Diff: 16.9% 95% CI, 6.1–27.6 Diff: 39.9% 95% CI, 23.9–55.9 4.1 (n=118)(n=115) (n=49) (n=50) 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 Time (months) Progression-FreeSurvival (probability) 182 93 37 20 8 1 1 0 0Chemo No. at risk 179 140 88 49 18 4 1 1 0Chemo + Bev 3.4 6.7 Progression-Free Survival1 Chemo Chemo + Bev Median PFS, mo 3.4 6.7 HR (95% CI) 0.48 (0.38–0.60) P value P<0.001 Bev=bevacizumab; CI=confidence interval; diff=difference; PFS=progression-free survival; QoL=quality of life. 1. Pujade-Lauraine E et al. J Clin Oncol. 2014;32(13):1302-1308. 2. Stockler MR et al. J Clin Oncol. 2014;32(13):1309-1316. Patient-Reported Outcomes2 Chemo Chemo + Bev
  • 20. Bevacizumab for Patients With Relapsed Ovarian Cancer for Whom Platinum Is Not an Option Improved PFS and ORR by adding bevacizumab to single-agent chemotherapy was observed across all chemotherapy cohorts 60 50 40 20 0 Paclitaxel cohort Topotecan cohort ORR(RECIST,CA-125 criteria,orboth)(%) 30 10 PLD cohort Diff: 22.9 95% CI, 3.9-41.8 51.7 28.8 18.37.9 22.8 3.3 Diff: 10.4 95% CI, -2.4–23.2 Diff: 19.5 95% CI, 6.7-32.3 1.00 0.75 0.50 0.25 0 0 3 6 9 12 15 18 21 24 Time (months) Progression-FreeSurvival (proportion) HR = 0.46 (95% CI, 0.30–0.71) 3.9 10.4 1.00 0.75 0.50 0.25 0 0 3 6 9 12 15 18 Time (months) Progression-Free Survival(proportion) HR=0.57 (95% CI, 0.39-0.83)5.4 3.5 1.00 0.75 0.50 0.25 0 0 3 6 9 12 15 Time (months) Progression-FreeSurvival (proportion) HR = 0.32 (95% CI, 0.21-0.49) 2.1 5.8 Chemo Chemo + Bev Bev=bevacizumab; CI=confidence interval; diff=difference; ORR=overall response rate; PFS=progression-free survival; PLD=pegylated liposomal doxorubicin; RECIST=Response Evaluation Criteria In Solid Tumours. Poveda AM et al. Presented at: ESMO Annual Meeting; 2012. PFS: Paclitaxel Cohort PFS: Topotecan Cohort PFS: PLD Cohort Overall Response Rates AURELIA: Practice Changing Trial ≤2 prior lines, Exclusion: platinum-refractory, prior (sub)obstruction, or bowel involvement N=360, randomised 1:1
  • 22. Beginning with a tumour test rather than a germline test: • Fewer patients will require two rounds of BRCA testing (a greater number of women with ovarian cancer will test negative on germline testing than will test positive on tumour testing). More cost-effective? • Consent may be perceived as more straightforward • Potential risk of not obtaining an accurate result (technical issues): missing a BRCA mutation BRCA Testing (Germline or Tumour): Standard of Care1-5 Current perspectives on recommendations for BRCA genetic testing in ovarian cancer patients. 1. Vergote I et al. Eur J Cancer. 2016;69:127-134. 2. NCCN Guidelines. https://www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf. Accessed 24 September 2018. 3. SGO. https://www.sgo.org/clinical-practice/guidelines/genetic-testing-for-ovarian-cancer/. Accessed 24 September 2018. 4. ASCO. https://www.asco.org/practice-guidelines/cancer-care- initiatives/genetics-toolkit/assessing-your-patient%E2%80%99s-hereditary. Accessed 24 September 2018. 5. Ledermann JA et al. https://www.esmo.org/Guidelines/Gynaecological-Cancers/Newly- Diagnosed-and-Relapsed-Epithelial-Ovarian-Carcinoma/eUpdate-Treatment-Recommendations. Accessed 24 September 2018. A patient with ovarian cancer who is BRCA Wild type on germline testing would need a subsequent tumour testing to establish whether or not she has a somatic BRCA mutation to access olaparib A patient with ovarian cancer who has a BRCA mutation identified from tumour testing would need subsequent germline testing to determine whether there are implications for her relatives Germline test Tumour test Negative Tumour test Germline test Positive
  • 23. Need to improve response rate, PFS, TFST, TSST, OS, and the cure rate Delay the psychological burden of disease progression Delay the physical symptoms associated with progressive disease Why? All newly diagnosed patients following first-line therapy AND All patients who have relapsed Who? A therapy that is effective and has convenient administration, limited impact on QoL, and limited toxicity What? Unmet Needs for Patients With Newly Diagnosed and Relapsed Ovarian Cancer Maintenance PARP inhibitors are a significant step forward in tackling the unmet need for women with ovarian cancer OS=overall survival; PFS=progression-free survival; QoL=quality of life; TFST=time to first subsequent therapy or death; TSST=time to second subsequent therapy or death.
  • 24. PARP Inhibitors Trap PARP, Preventing the Repair of SSBs Which Are Then Converted to DSBs 24 Increase in double- strand breaks in replicating cells Double-strand breaks Trapped PARP on single-strand breaks PARP PARPi DSB=double-strand break; PARPi=PARP inhibitor; SSB=single-strand break. O’Connor MJ. Mol Cell. 2015;60(4):547-560.
  • 25. In HRD Cells, Where Deficiencies in DSB Repair Exist, the Cells Cannot Cope With the Increase in DSBs and This Leads to Cell Death 25 HRR-deficient cancer cell Increase in double- strand breaks in replicating cells Trapped PARP on single-strand breaks Double-strand breaks Normal cell Repair of double-strand breaks via the HR pathway and cell survival PARP PARPi ✓ Reliance on error-prone pathways leads to DNA damage accumulation and cell death  DSB=double-strand break; HR=homologous recombination; HRD=HR deficient; HRR=HR repair. O’Connor MJ. Mol Cell. 2015;60(4):547-560.
  • 26. Rationale for PARP Inhibitors in Ovarian Cancer: High-Grade Serous Ovarian Cancer Biology HRR=homologous recombination repair. Hollis RL et al. Cancer Biol Med. 2016;13:236-247. 26 8% 6% 4% 3% 11% 6% <5% 14% 7% 20% 17% Germline BRCA1 Germline BRCA2 Somatic BRCA1 Somatic BRCA2 BRCA1 methylation EMSY amplification Other HRR genes CCNE1 amplification PTEN loss RB1 loss NF1 loss TP53 mutation HRR Proficient HRR Deficient
  • 27. Olaparib1-8 Niraparib9,10 Rucaparib11,12 Indications EU, Australia, Canada Japan, Taiwan & China: • Maintenance treatment of PSR ovarian cancer +/- BRCAm US & India: • Maintenance treatment of PSR ovarian cancer +/- BRCAm • gBRCAm ovarian cancer after ≥3 lines of chemotherapy EU & US: • Maintenance treatment of PSR ovarian cancer +/- BRCAm EU: • BRCAm ovarian cancer after ≥2 lines of chemotherapy US: • Maintenance treatment of PSR ovarian cancer +/- BRCAm • BRCAm ovarian cancer after ≥2 lines of chemotherapy Dosing 300 mg (2 tablets*) BID 400 mg (8 capsules*) BID 300 mg (3 capsules) QD 600 mg (2 tablets) BID Additional Indications US, Australia, Canada, India & Japan: • gBRCAm, HER2-ve mBC following chemotherapy PARP Inhibitors Approved for Ovarian Cancer *Olaparib capsules and tablets are not interchangeable. BID=twice daily; BRCAm=BRCA mutated; gBRCAm=germline BRCAm; HER2=human epidermal growth factor receptor 2; QD=once daily; PSR=platinum-sensitive relapsed. 1. LYNPARZA (prescribing information). AstraZeneca; 2018. 2. LYNPARZA (SmPC). AstraZeneca, 2018. 3. LYNPARZA (product monograph). AstraZeneca; 2018. 4. AstraZeneca [press release]. https://www.astrazeneca.com/media-centre/press-releases/2018/lynparza-receives-approval-in-japan-for-the-treatment-of-advanced-ovarian-cancer-19012018.html. Accessed 31 August 2018. 5. Biocentury. China approves Lynparza in ovarian cancer. https://www.biocentury.com/bc-extra/company-news/2018-08-23/china-approves-lynparza-ovarian-cancer. Accessed 31 August 2018. 6. Astrazeneca Pharma India Ltd. https://www.bseindia.com/xml-data/corpfiling/AttachLive/96ccdd40-16ae-46d0-b332-6e8991aa8bc9.pdf. Accessed 31 August 2018 7. AstraZenenca (press release). https://www.astrazeneca.com/media- centre/press-releases/2018/lynparza-approved-in-japan-for-brca-mutated-metastatic breast-cancer-02072018.html. Accessed 31 August 2018. 8. LYNPARZA olaparib 150 mg film coated tablet blister pack. https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=2D8DEBA19DE565EFCA2582E2004244D5&agid=(PrintDetailsPublic)&actionid=1. Accessed 31 August 2018 9. ZEJULA (summary of product characteristics). Tesaro; 2017. 10. ZEJULA (prescribing information). Tesaro; 2018. 11. RUBRACA (summary of product characteristics). Clovis; 2018. 12. RUBRACA (prescribing information). Clovis; 2018. 27 Veliparib and talazoparib are not approved for use in ovarian cancer.
  • 29. ENGOT-ov16/NOVA: Study Design 29 Stratification factors: • TTP on penultimate platinum therapy (6 to <12 months vs ≥12 months) • Prior bevacizumab treatment • Best response (complete or partial) during the last platinum regimen Niraparib 300 mg QD until progression/toxicity Placebo QD until progression/toxicity Patients • PSR high grade serous ovarian* cancer • ≥2 lines of platinum-based therapy • Achieved a CR or PR • No measurable disease <2 cm • CA 125 in the normal range (or decreased by more than 90% during last regimen and stable for at least 7 days) gBRCAm Randomise 2:1 n=203 Non-gBRCAm* Randomise 2:1 n=350 Niraparib 300 mg QD until progression/toxicity Placebo QD until progression/toxicity *Includes sBRCAm patients. CR=complete response; gBRCAm=germline BRCA mutated; PR=partial response; PSR=platinum-sensitive relapsed; QD=once daily; TTP=time to progression. 1. Mirza MR et al. N Engl J Med. 2016;375(22):2154-2164. 2. Mirza MR et al. N Engl J Med. 2016;375(22):2154-2164. Supplementary appendix.
  • 30. No. at Risk Niraparib 138 125 107 98 89 79 63 44 28 26 16 3 1 Placebo 65 52 34 21 12 8 6 2 2 2 1 1 0 ENGOT-ov16/NOVA: BICR-Assessed Progression-Free Survival 30 BICR=blinded independent central review; CI=confidence interval; gBRCAm=germline BRCA mutated; HR=hazard ratio; PFS=progression-free survival. 1. Mirza MR et al. N Engl J Med. 2016;375(22):2154-2164. 2. Center for Drug Evaluation and Research. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208447Orig1s000 MultidisciplineR.pdf. Accessed 13 September 2018. 24 gBRCAm1 100 75 50 25 0 Time from Randomisation (months) 121086420 14 16 18 20 22 Progression-FreeSurvival(%) Niraparib Placebo Niraparib Placebo Median, mo 21.0 5.5 HR (95% CI) 0.27 (0.17–0.41) Median, mo 14.8 5.5 HR (95% CI) 0.27 (0.18–0.40) BICR assessed1 Investigator assessed2 No. at Risk Niraparib 234 188 145 113 88 75 57 41 23 21 16 7 3 Placebo 116 88 52 33 23 19 10 8 4 4 3 1 1 Time from Randomisation (months) Non-gBRCAm1 100 75 50 25 0 121086420 14 16 18 20 22 24 Progression-FreeSurvival(%) Niraparib Placebo Niraparib Placebo Median, mo 9.3 3.9 HR (95% CI) 0.45 (0.34–0.61) P value P<0.001 BICR assessed1
  • 31. ARIEL3: Study Design 31 Patients • PSR high-grade serous or endometrioid epithelial ovarian cancer • ≥2 prior platinum-based treatment regimens • ≤1 non-platinum chemotherapy regimen • CR or PR to last course of chemotherapy Rucaparib 600 mg BID until progression/toxicity n=375 Primary endpoint: Investigator- assessed PFS in: • tBRCAm • HRD • Intent-to-treat population Secondary endpoints: • PFS (BICR) • PROs • Population PK • Overall survival • Safety and tolerability Placebo BID until progression/toxicity n=189 Randomise 2:1 N=564 Stratification factors: • HRR gene status • Time to progression with penultimate platinum therapy • Response to last platinum BICR=blinded independent central review; BID=twice daily; CR=complete response; HRD=homologous recombination deficient; PFS=progression-free survival; PK=pharmacokinetics; PR=partial response; PRO=patient-reported outcome; PSR=platinum-sensitive relapsed; tBRCAm=tumour BRCA mutated. Coleman RL et al. Lancet. 2017;390(10106):1949-1961.
  • 32. The primary endpoint was investigator-assessed PFS (per RECIST) • BRCAm and LOH in tumour samples were measured using Foundation Medicine’s T5 NGS assay 32 ARIEL-3: Primary Endpoint and Step-Down Analysis Germline or somatic BRCA mutation Germline or somatic BRCA mutation + BRCA wild-type/LOH high (≥16% genomic LOH prespecified) Germline or somatic BRCA mutation + BRCA wild-type/LOH high + BRCA wild-type/LOH low + BRCA wild-type/LOH indeterminate If significant* BRCAm HRD+ ITT (all comers) If significant* *Investigator-assessed PFS at a one-sided 0.025 significance level. Visit cutoff date for all analyses: 15 April 2017. BRCAm=BRCA mutated; HRD=homologous recombination deficient; ITT=intent-to-treat; LOH=loss of heterozygosity. Coleman RL et al. Lancet. 2017;390(10106):1949-1961.
  • 33. No. at Risk (censored) Niraparib 130 (0) 93 (14) 63 (21) 35 (37) 15 (51) 3 (60) 0 (63) Placebo 66 (0) 24 (5) 6 (7) 3 (8) 1 (9) 0 (10) 0 (10) ARIEL-3: Progression-Free Survival of Patients With BRCAm 33 BID=twice daily; BRCAm=BRCA mutated; CI=confidence interval; HR=hazard ratio. Coleman RL et al. Lancet. 2017;390(10106):1949-1961. Time from Randomisation (months) 36 Primary Endpoint: Investigator-Assessed PFS 181260 24 30 100 75 50 25 0 Rucaparib Placebo Progression-FreeSurvival(%) Rucaparib BID Placebo BID Median, mo 16.6 5.4 HR (95% CI) 0.23 (0.16–0.34) Median, mo 26.8 5.4 HR (95% CI) 0.20 (0.13–0.32) Investigator assessed BICR assessed
  • 34. No. at Risk (censored) Niraparib 375 (0) 228 (36) 128 (61) 65 (93) 26 (123) 5 (136) 0 (141) Placebo 118 (0) 63 (12) 7 (18) 7 (18) 2 (20) 1 (21) 0 (22) No. at Risk (censored) Niraparib 236 (0) 161 (20) 96 (36) 54 (60) 21 (86) 5 (97) 0 (102) Placebo 118 (0) 40 (10) 11 (12) 6 (14) 1 (16) 0 (17) 0 (17) ARIEL-3: Investigator-Assessed PFS of HRD+ Patients and the ITT Population 34 Treatment PFS Median, mo HR (95% CI) P value Rucaparib (n=375) 10.8 0.36 (0.30–0.45) P<0.0001 Placebo (n=189) 5.4 Treatment PFS Median, mo HR (95% CI) P value Rucaparib (n=236) 13.6 0.32 (0.24–0.42) P<0.0001 Placebo (n=118) 5.4 BRCAm=BRCA mutated; CI=confidence interval; HR=hazard ratio; HRD=homologous recombination deficient; ITT=intent-to-treat; PFS=progression-free survival. Coleman RL et al. Lancet. 2017;390(10106):1949-1961. Time from Randomisation (months) ITT 181260 24 30 36 100 75 50 25 0 Rucaparib Placebo Progression-FreeSurvival(%) HRD+ Time from Randomisation (months) 181260 24 30 36 100 75 50 25 0 Rucaparib Placebo Progression-FreeSurvival(%)
  • 35. Summary 35 PARPi therapy is one of the most important advances for ovarian cancer patients in the past decades Maintenance with niraparib or rucaparib significantly improves progression-free survival after platinum response in platinum-sensitive relapsed ovarian cancer. However, no direct comparison is possible due to differences in study designs1,2 BRCAm patients benefit most, but no predictive NGS test is sensitive enough to rule out the benefit for BRCAwt patients who have platinum-sensitive relapsed ovarian cancer1,2 Treatment-emergent adverse events with niraparib or rucaparib were generally managed with dose modifications (67% and 55%, respectively), and the rate of discontinuation was low (15% and 13%, respectively)1,2 Note: In the absence of head-to-head data between PARPi efficacy and safety comparisons between PARPi are not to be made or communicated. BRCAm=BRCA mutated; BRCAwt=BRCA wild type; NGS=next-generation sequencing; PARPi=PARP inhibitor. 1. Mirza MR et al. N Engl J Med. 2016;375(22):2154-2164. 2. Coleman RL et al. Lancet. 2017;390(10106):1949-1961.
  • 36. SOLO-2, a phase 3 study, was designed to provide additional evidence for the benefit of olaparib maintenance therapy in patients with BRCAm PSR ovarian cancer1,2 • SOLO-2 reported data on the new film-coated tablet formulation of olaparib1-3 • The tablet formulation used in SOLO-2 was chosen based on data from Study 244 • The recommended tablet dose was 300 mg administered as 2 x 150-mg tablets, twice daily4 36 SOLO-2: Study Design Placebo n=99 Olaparib 300 mg BID tablets n=196 Primary endpoint: Investigator-assessed PFS 2:1 randomisation Patients: • PSR SOC and BRCA1/2 mutation • ≥2 prior lines of platinum therapy • CR or PR to most recent therapy1 BID=twice daily; BRCAm=BRCA mutated; CR=complete response; PFS=progression-free survival; PR=partial response; PSR=platinum-sensitive relapsed; SOC=standard of care. 1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01874353. Accessed 24 September 2018. 2. Pujade-Lauraine E et al. Lancet Oncol. 2017;18(9):1274-1284. 3. Ledermann J et al. N Engl J Med. 2012;366:1382–1392. 4. Mateo J et al. Target Oncol. 2016;11(3):401–415.
  • 37. Risk of progression or death during the study was reduced by 70% for patients taking olaparib vs placebo1.2 37 SOLO-2: Investigator-Assessed Progression-Free Survival 36 Olaparib Placebo No. at Risk Investigator-assessed PFS at 63% maturity. Median follow-up for PFS was 22.1 months in the olaparib group and 22.2 months for placebo. Full assessment set N=295. Data cutoff: 9/19/2016. BID=twice daily; CI=confidence interval; HR=hazard ratio; PFS=progression-free survival. 1. Pujade-Lauraine E et al. Lancet Oncol. 2017;18(9):1274-1284. 2. Pujade-Lauraine E et al. Presented at: SGO Annual Meeting; 2017. 196 99 89 14 104 17 118 18 134 22 156 37 182 70 82 12 32 7 29 6 2 0 0 0 Olaparib 300 mg BID tablets Placebo BID Investigator-Assessed PFS Time from Randomisation (months) 1815129630 21 24 27 33 ProportionofPatientsProgressionFree 0.0 0.2 0.4 0.6 0.8 1.0 30 3 0 Olaparib 300 mg BID tablets Placebo BID Events, n (%) 107/196 (54.6) 80/99 (80.8) Median PFS, mo 19.1 5.5 HR=0.30 (95% CI, 0.22–0.41) P<0.0001
  • 38. Over their first two years of treatment, almost 70% of patients were able to remain on 300 mg BID tablets 38 SOLO-2: The Majority of Patients Remained on Starting Dose of Olaparib (300 mg BID Tablets) 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Treatment Month 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 ProportionofPatients 195 190 189 182 175 169 156 153 147 139 134 129 122 121 115 110 108 104 101 100 97 94 92 77 Number of patients treated: 200 mg BID tablets 300 mg BID tablets 250 mg BID tablets Other regimen* No dosing** Denominator for each month is the number of patients treated at the start of the month or after. Each patient is counted at the first non-missing dose level within the given month window. *Included: 150 mg QD, 200 mg QD, 250 mg QD, 300 mg QD, 150 mg BID, 150 mg TID. **If the patient had dosing interrupted for the entire month window, the category of no dosing was assigned. BID=twice daily; QD=once daily; TID=three times daily Korach J et al. Presented at: ESMO Annual Meeting; 2018.
  • 39. SOLO-2: • There was no appreciable difference in quality of life for patients receiving olaparib (300 mg BID tablets*) compared with those receiving placebo, as assessed with the TOI score derived from the FACT-O questionnaire2 • Additional analyses of QAPFS and TWiST (Time Without Symptom or Toxicity) demonstrated a significant improvement for patients in the olaparib treatment group (300 mg BID tablets*) compared with placebo3 Study 19: • There were no significant differences in disease-related symptoms or rates of improvement in HRQoL with olaparib (400 mg BID capsules*) and placebo, as measured by scores on the FACT–O questionnaire, NCCN-FACT Ovarian Symptom Index, and TOI1 Study 19 and SOLO-2: Health-Related Quality of Life (HRQoL) *Olaparib capsules and tablets are not interchangeable. BID=twice daily; FACT-O=Functional Assessment of Cancer Therapy-Ovarian Cancer; NCCN-FACT=National Comprehensive Cancer Network–FACT; QAPFS=quality-adjusted progression-free survival; TOI=Trial Outcome Index; TWiST=time without symptoms of disease or toxicity. 1. Ledermann J et al. N Engl J Med. 2012;366:1382–1392. 2. Pujade-Lauraine E et al. Lancet Oncol. 2017;18(9):1274–1284. 3. Friedlander M et al. J Clin Oncol. 2017;35(suppl):5507. Time from Randomisation (months) Probability 1.0 0.8 0.6 0.4 0.2 0.0 0 3 6 9 12 15 18 21 24 27 Olaparib 300 mg BID tablets TWiST Toxicity Time from Randomisation (months) 1.0 0.8 0.6 0.4 0.2 0.0 0 3 6 9 12 15 18 21 24 27 Placebo BID Probability TWiST Toxicity Olaparib 300 mg BID tablets, mo n=185 Placebo BID, mo n=94 Difference (95% CI) P value TWiST 13.5 7.21 6.29 (2.95–8.58) <0.0001 Toxicity 3.69 0.71 2.98 (1.52–4.68) 0.0002
  • 40. Bevacizumab Is Here in Frontline—What About PARPi? Phase III PRIMA: NCT02655016 Niraparib maintenance for newly diagnosed advanced OC Niraparib4 Olaparib + Bev3 Phase III PAOLA-1: NCT02477644 Olaparib + Bev maintenance for newly diagnosed advanced OC Phase III SOLO-1: NCT01844986 Olaparib maintenance for newly diagnosed advanced BRCAm OCOlaparib1 Phase III GOG-3005: NCT02470585 PC +/- concurrent and maintenance veliparib for newly diagnosed advanced OC Bev=bevacizumab; BRCAm=BRCA mutated; OC=ovarian cancer; PARPi=PARP inhibitor; PC=paclitaxel and carboplatin. 1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01844986. Accessed 1 October 2018. 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02470585. Accessed 1 October 2018. 3. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02477644. Accessed 1 October 2018. 4. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02655016. Accessed 1 October 2018. Veliparib2
  • 41. SOLO-1: PHASE III TRIAL OF MAINTENANCE OLAPARIB FOLLOWING PLATINUM-BASED CHEMOTHERAPY IN NEWLY DIAGNOSED PATIENTS WITH ADVANCED OVARIAN CANCER AND A BRCA1/2 MUTATION 1Stephenson Oklahoma Cancer Center, Oklahoma City, OK, USA; 2University of Milan-Bicocca and IEO, European Institute of Oncology IRCCS, Milan, Italy; 3Fondazione Policlinico Universitario A. Gemelli IRCCS Università Cattolica, Rome, Italy; 4Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 5Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; 6University of New South Wales Clinical School, Prince of Wales Hospital, Randwick, Australia; 7St Petersburg City Oncology Dispensary, St Petersburg, Russia; 8Institut Bergonié, Comprehensive Cancer Centre, Bordeaux, France; 9Gustave-Roussy Cancer Campus, Villejuif, France; 10The Netherlands Cancer Institute, Amsterdam, The Netherlands; 11Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK; 12The Royal Marsden NHS Foundation Trust, London, UK; 13Princess Margaret Cancer Centre, Toronto, ON, Canada; 14MD Anderson Cancer Centre Madrid, Madrid, Spain; 15Memorial Sloan Kettering Cancer Center, New York, NY, USA; 16Froedtert and the Medical College of Wisconsin, Milwaukee, WI, USA; 17AstraZeneca, Gaithersburg, MD, USA; 18AstraZeneca, Cambridge, UK; 19Women & Infants Hospital, Providence, RI, USA Kathleen Moore,1 Nicoletta Colombo,2 Giovanni Scambia,3 Byoung-Gie Kim,4 Ana Oaknin,5 Michael Friedlander,6 Alla Lisyanskaya,7 Anne Floquet,8 Alexandra Leary,9 Gabe S. Sonke,10 Charlie Gourley,11 Susana Banerjee,12 Amit Oza,13 Antonio González-Martín,14 Carol Aghajanian,15 William Bradley,16 Elizabeth S. Lowe,17 Ralph Bloomfield,18 Paul DiSilvestro19 ClinicalTrials.gov identifier: NCT01844986. This study was sponsored by AstraZeneca; part of an alliance between AstraZeneca and Merck & Co., Inc.
  • 42. SOLO-1: Study Design Upfront or interval attempt at optimal cytoreductive surgery for stage III disease and either biopsy and/or upfront or interval cytoreductive surgery for stage IV disease. BICR=blinded independent central review; BID=twice daily; ECOG=Eastern Cooperative Oncology Group; FACT-O=Functional Assessment of Cancer Therapy – Ovarian Cancer; FIGO=International Federation of Gynecology and Obstetrics; HRQoL=health-related quality of life; PFS=progression-free survival; PFS2=time to second progression or death; RECIST=Response Evaluation Criteria In Solid Tumours; TOI=Trial Outcome Index. Moore K et al. Presented at: ESMO annual meeting; 2018. • Newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer and/or fallopian tube cancer • Germline or somatic BRCAm • ECOG performance status 0–1 • Cytoreductive surgery • Completed platinum-based chemotherapy • In clinical complete response or partial response Primary endpoint • Investigator-assessed PFS (modified RECIST 1.1) Secondary endpoints • PFS using BICR • PFS2 • Overall survival • Time from randomisation to first subsequent therapy or death • Time from randomisation to second subsequent therapy or death • HRQoL (FACT-O TOI score) Olaparib 300 mg BID (n=260) Placebo (n=131) • Study treatment continued until disease progression • Patients with no evidence of disease at 2 years stopped treatment • Patients with a partial response at 2 years could continue treatment 2:1 randomisation Stratified by response to platinum-based chemotherapy
  • 43. Olaparib (n=260) Placebo (n=131) Events (%) 102 (39.2) 96 (73.3) Median PFS, mo NR 13.8 HR=0.30 95% CI, 0.23–0.41 P<0.0001 SOLO-1: PFS by Investigator Assessment (50.6% Maturity) CI=confidence interval; NR=not reached; HR=hazard ratio; PFS=progression-free survival. Moore K et al. Presented at: ESMO annual meeting; 2018. 0 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 0 10 20 30 40 50 60 70 80 90 100 3 Investigator-Assessed Progression-FreeSurvival(%) Time from Randomisation (months) 260 131 229 103 221 82 212 65 201 56 194 53 184 47 172 41 149 39 138 38 133 31 111 28 88 22 45 6 36 5 4 1 3 0 0 0 0 0 0 0 240 118 No. at risk Olaparib Placebo Olaparib Placebo
  • 44. SOLO-1: PFS Landmark Analysis 87.7 51.4 73.6 34.6 60.4 26.9 52.6 11.4 Based on Kaplan-Meier estimates, after 3 years, 60.4% of patients in the olaparib arm were progression-free compared with 26.9% of patients in the placebo arm 12 months 0 10 20 30 40 50 60 70 80 90 100 FreeofProgressionorDeath(%) 24 months 36 months 48 months Olaparib Placebo PFS=progression-free survival. Moore K et al. Presented at: ESMO annual meeting; 2018.
  • 45. 11.5 26.9 3.8 19.2 24.6 10 14.6 41.5 37.7 23.1 25.4 26.2 27.7 34.2 38.8 40.0 63.5 77.3 SOLO-1: Most Common Treatment-Emergent Adverse Events Olaparib (n=260) Placebo (n=130) Adverse events (%) Constipation Dysgeusia Neutropenia* Nausea Fatigue/asthenia* Vomiting Diarrhoea Arthralgia Anaemia* 0.8 3.8 0.4 21.5 3.1 8.5 4.6 1.5 0.8 1.5 All grades (frequency ≥25%) Grade ≥3 (frequency ≥5%) All grades (frequency ≥25%) Grade ≥3 (frequency ≥5%) *Grouped terms. All-grade thrombocytopenia (grouped term) occurred in 11.2% of patients in the olaparib group and 3.8% of patients in the placebo group and grade ≥3 thrombocytopenia (grouped term) occurred in 0.8% and 1.5%, respectively. Moore K et al. Presented at: ESMO annual meeting; 2018. 100 75 50 25 0 0 25 50 75 100
  • 47. *Includes patients with primary peritoneal and/or fallopian tube cancer. †Tablet formulation (2 tablets twice daily). ECOG=Eastern Cooperative Oncology Group; FIGO=International Federation of Gynecology and Obstetrics; gBRCAm=germline BRCA mutation; HRQoL=health-related quality of life; OS=overall survival; PFS1=time to first progression; PFS2=time to second progression; PRO=patient-reported outcome; PS=performance status; RECIST=Response Evaluation Criteria In Solid Tumours; TSST=time to second subsequent therapy. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02470585. Accessed 1 October 2018. VELIA: Phase 3 Trial of Veliparib With Carboplatin and Paclitaxel as Continuous Maintenance FIGO stage III–IV high-grade ovarian cancer (serous)* or non-mucinous BRCAm ECOG PS 0–1 gBRCA testing prior to randomisation Randomise 1:1 N≈1140 Primary endpoint • PFS1 (RECIST 1.1) Secondary endpoints • PFS2 • TSST • OS • Safety • PRO/HRQoL Veliparib + Carboplatin and Paclitaxel → Veliparib maintenance Placebo Carboplatin and Paclitaxel → Placebo maintenance Stratify by: • BRCA status Status: Completed enrolment
  • 48. PAOLA-1: Phase 3 Trial of Olaparib vs Placebo Plus Bevacizumab as Maintenance Treatment in Patients With Advanced Ovarian Cancer FIGO stage III–IV high- grade ovarian cancer (serous or endometrioid)* or non-mucinous BRCAm No evidence of disease or CR or PR following first-line platinum-based chemotherapy plus bevacizumab A minimum of 3 cycles of platinum-based chemotherapy plus bevacizumab (2 after interval debulking) ECOG PS 0–1 BRCA testing prior to randomisation Randomise 2:1 N≈806 European + 24 Japanese patients Primary endpoint • PFS1 (RECIST 1.1) Secondary endpoints • PFS2 • TSST • OS • Safety • PRO/HRQoL Olaparib 300 mg† PO BID + bevacizumab 15 mg/kg Q3W 15 months Placebo + bevacizumab 15 mg/kg Q3W 15 months Stratify by: • tBRCA status • CR/PR/NED Status: Completed enrolment *Includes patients with primary peritoneal and/or fallopian tube cancer. †Tablet formulation (2 tablets twice daily). BID=twice daily; BRCAm=BRCA mutation; CR=complete response; ECOG=Eastern Cooperative Oncology Group; FIGO=International Federation of Gynecology and Obstetrics; HRQoL=health-related quality of life; NED=no evidence of disease; OS=overall survival; PFS1=time to first progression; PFS2=time to second progression; PO=by mouth; PR=partial response; PRO=patient-reported outcome; PS=performance status; Q3W=every 3 weeks; RECIST=Response Evaluation Criteria In Solid Tumours; tBRCA=tumour BRCA; TSST=time to second subsequent therapy. 1. Ray-Coquard IL et al. J Clin Oncol. 2017;35(15_suppl). 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02477644. Accessed 1 October 2018. • Study treatment continued until disease progression • Patients with no evidence of disease at 2 years stopped treatment • Patients with a partial response at 2 years could continue treatment
  • 49. *Includes patients with primary peritoneal and/or fallopian tube cancer. †Tablet formulation (2 tablets twice daily). BRCAm=BRCA mutation; CR=complete response; ECOG=Eastern Cooperative Oncology Group; FIGO=International Federation of Gynecology and Obstetrics; HRD=homologous recombination deficiency; HRQoL=health-related quality of life; NED=no evidence of disease; OS=overall survival; PFS1=time to first progression; PFS2=time to second progression; PO=by mouth; PR=partial response; PRO=patient-reported outcome; PS=performance status; Q3W=every 3 weeks; QD=once daily; RECIST=Response Evaluation Criteria In Solid Tumours; TSST=time to second subsequent therapy. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02655016. Accessed 1 October 2018 PRIMA: Phase 3 Trial of Niraparib vs Placebo as Maintenance Treatment in Patients With Advanced Ovarian Cancer FIGO stage III–IV high-grade ovarian cancer (serous or endometrioid)* or non-mucinous BRCAm CR or PR following first-line platinum-based chemotherapy Stage IV patients are eligible, irrespective of residual disease. Stage III patients are required to have visible residual disease after primary surgery HRD testing prior to randomisation Randomise 2:1 N≈620 Primary endpoint • PFS1 (RECIST 1.1) Secondary endpoints • PFS2 • TSST • OS • Safety • PRO/HRQoL Niraparib 300 mg† PO QD PlaceboStratify by: • HRD status • CR/PR/NED Status: Completed enrolment
  • 50. Overview of Studies Evaluating PARPi in Frontline Maintenance SOLO-11,2 PAOLA-13,4 PRIMA5 Key Inclusion Criteria Germline or somatic BRCAm Regardless of BRCAm Regardless of BRCAm; Stage III patients are required to have visible residual disease after surgery Treatment Arms Olaparib vs placebo Olaparib + bevacizumab vs placebo + bevacizumab Niraparib vs placebo Prior Treatment NED/CR/PR following first-line platinum-based chemotherapy NED/CR/PR following first-line platinum-based chemotherapy + bevacizumab CR/PR following first-line platinum-based chemotherapy Treatment Duration 24 months* Bevacizumab for 15 months and olaparib for 24 months* Until disease progression Current Status of Trial Primary endpoint met Enrolment complete Enrolment complete *Or until disease progression. BRCAm=BRCA mutation; CR=complete response; NED=no evidence of disease; PR=partial response. 1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01844986. Accessed 1 October 2018. 2. AstraZeneca Press Release. https://www.astrazeneca.com/media-centre/press- releases/2018/lynparza-significantly-delays-disease-progression-in-phase-iii-1st-line-solo-1-trial-for-ovarian-cancer.html. Accessed 3 October 2018. 3. Ray-Coquard IL et al. J Clin Oncol. 2017;35(15_suppl). 4. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02477644. Accessed 1 October 2018. 5. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02655016. Accessed 1 October 2018.
  • 51. Bevacizumab and PARPi Are Here in Frontline— What About Immunotherapy? Bev=bevacizumab; BRCAm=BRCA mutated; OC=ovarian cancer; PARPi=PARP inhibitor; PC=paclitaxel and carboplatin. 1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01844986. Accessed 1 October 2018. 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02470585 . Accessed 1 October 2018. 3. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02477644. Accessed 1 October 2018. 4. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02655016. Accessed 1 October 2018. Phase III PRIMA: NCT02655016 Niraparib maintenance for newly diagnosed advanced OCNiraparib4 Olaparib + Bev3 Phase III PAOLA-1: NCT02477644 Olaparib + Bev maintenance for newly diagnosed advanced OC Phase III SOLO-1: NCT01844986 Olaparib maintenance for newly diagnosed advanced BRCAm OCOlaparib1 Phase III GOG-3005: NCT02470585 PC +/- concurrent and maintenance veliparib for newly diagnosed advanced OC Veliparib2 What’s next?
  • 52. The Rationale for Targeting PD-L1 in Ovarian Cancer OC is associated with mutational burden1 Tumour mutations increase tumour-specific antigens2 >50% of OC tumours show tumour-infiltrating T cells at diagnosis3 Improved OC outcomes? Immunosuppressive tumour microenvironment Anti-PDL1 or anti-PD1 OC=ovarian cancer; PD-1=programmed death-1; PD-L1=programmed death-ligand 1. 1. Lawrence MS et al. Nature. 2013;499(7457):214-218. 2. Strickland K et al. J Clin Oncol. 2015;33(15_suppl):5512. 3. Zhang L et al. N Engl J Med. 2003;348(3):203-213. 4. Hamanishi J et al. Proc Natl Acad Sci. 2007;104(9):3360-3365. 5. Abiko K et al. Clin Cancer Res. 2013;19(6):1363-1374. Increased expression of immune checkpoint modulators (PD-L1 and PD-1)4,5 as a potential mechanism of resistance
  • 53. Immunotherapies Are Coming Soon—What About in Combination With PARPi? Phase III PRIMA: NCT02655016 Niraparib maintenance for newly diagnosed advanced OCNiraparib4 Olaparib + Bev3 Phase III PAOLA-1: NCT02477644 Olaparib + Bev maintenance for newly diagnosed advanced OC Phase III SOLO-1: NCT01844986 Olaparib maintenance for newly diagnosed advanced BRCAm OCOlaparib1 Phase III GOG-3005: NCT02470585 PC +/- concurrent and maintenance veliparib for newly diagnosed advanced OC Bev=bevacizumab; BRCAm=BRCA mutated; IO=immuno-oncology; OC=ovarian cancer; PARPi=PARP inhibitor; PC=paclitaxel and carboplatin. 1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01844986. Accessed 1 October 2018. 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02470585. Accessed 1 October 2018. 3. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02477644. Accessed 1 October 2018. 4. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02655016. Accessed 1 October 2018. 5. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02718417. Accessed 2 October 2018. 6. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03038100. Accessed 11 October 2018. Veliparib2 Javelin 1005 Phase III JAVELIN OVARIAN-100: NCT02718417 Avelumab in combo with and/or following chemo for newly diagnosed advanced OC IMagyn0506 Phase III IMagyn050: NCT03038100 Chemo + Bev +/- atezolizumab for newly diagnosed advanced OC What about IO + PARPi?
  • 54. Block immunosuppression within the tumour microenvironment and enhance tumour cell death3 Anti-PDL1 Anti-PD1 Increase T-cell trafficking and infiltration into tumours1 Anti-VEGF Combination Opportunities in Ovarian Cancer: Immunotherapy and PARP Inhibition Enhance antigen presentation and T-cell activation2 Chemotherapy Radiotherapy PARPi RECRUIT/ INFILTRATE (vasculature) Non-inflamed ACTIVATE (central) Non-inflamed KILL CANCER CELLS (tumour) inflamed PARPi=PARP inhibitor; PD-1=programmed death-1; PD-L1=programmed death-ligand 1; VEGF=vascular endothelial growth factor. 1. Vanneman M et al. Nat Rev Cancer. 2012;12(4):237-251. 2. Brown JS. Br J Cancer. 2018;118(3):312-324. 3. Chen DS et al. Immunity. 2013;39(1):1-10. PARPi • Enhanced DNA damage and mutational load in tumour cells
  • 55. Overview of Ongoing Phase 3 Trials With Immunotherapy + PARPi for the Treatment of Ovarian Cancer ENGOT-ov44/ FIRST1 Javelin Ovarian 100 PARP2 ATHENA3 ENGOT-ov46/ DUO-O4 Patient Population Newly diagnosed advanced ovarian cancer Newly diagnosed advanced ovarian cancer Newly diagnosed advanced ovarian cancer Newly diagnosed advanced ovarian cancer Treatment Arms • Platinum + TSR-042 (PD-L1i) followed by niraparib + TSR-042 • Adaptive standard platinum-based treatment • Avelumab + chemo followed by avelumab + talazoparib • Chemo followed by talazoparib • Chemo + Bev followed by Bev • Rucaparib + nivolumab • Rucaparib + IV placebo • Nivolumab + oral placebo • Oral placebo + IV placebo • Chemo + durvalumab +/- bevacizumab followed by durvalumab + bevacizumab + olaparib Prior Treatment None None Platinum-based chemotherapy None Expected Primary Completion Date June 2020 February 2022 December 2024 — Bev=bevacizumab; IV=intravenous; PARPi=PARP inhibitor; PD-L1i=programmed death-ligand 1 inhibitor. 1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03602859. Accessed 19 October 2018. 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03642132. Accessed 2 October 2018. 3. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03522246. Accessed 3 October 2018. 4. ENGOT Ovarian Cancer Clinical Trials. https://engot.esgo.org/clinical- trials/current-clinical-trials/ovarian/. Accessed 3 October 2018.
  • 56. ✓ Most include active agent in combination with carboplatin-paclitaxel ✓ ATHENA is switch maintenance only IO study ✓ Three virtually identical studies (FIRST, ENGOT-ov43, ENGOT-ov46/DUO-O) ✓ Others incorporate active agents in both treatment and as maintenance (continuous or switch) The Frontline Ovarian Cancer Space Is a Crowded Landscape! First-Line Treatment with Maintenance First-Line Switch Maintenance First-Line Treatment/ Maintenance with IO First-Line Treatment/ Maintenance with IO and PARPi GOG 218 SOLO-1 FIRST FIRST Javelin Ovarian 100 PAOLA-1 ENGOT-ov43 ENGOT-ov43 Javelin Ovarian 100 PARP PRIMA ENGOT-ov46/DUO-O ENGOT-ov46/DUO-O VELIA 3005 ATHENA ATHENA ATHENA IMagyn50 3015 Javelin Ovarian 100 Javelin Ovarian 100 PARP FIRST Javelin Ovarian 100 PARP ENGOT-ov43 IMagyn50 3015 ENGOT-ov46/DUO-O IO=immuno-oncology; PARPi=PARP inhibitor. Slide courtesy of Brad Monk, MD.
  • 57. What’s the Status of Frontline Trials? Planned Actively Enrolling Closed—Results Pending Completed FIRST ATHENA VELIA 3005 GOG218 ENGOT-ov43 IMagyn050 3015 PAOLA-1 ICON7 ENGOT-ov46/DUO-O JAVELIN Ovarian 100 PARP PRIMA SOLO-1 Javelin Ovarian 100 JAVELIN 200 (Recurrent) FORWARD- 1 (Recurrent) Slide courtesy of Brad Monk, MD.
  • 58. Frontline treatment is becoming more challenging • Bevacizumab is here—is it for everyone? • Olaparib is here for BRCAm (SOLO-1) • Olaparib + bevacizumab trial ongoing (PAOLA-1) • Niraparib trial ongoing (PRIMA) Frontline treatment choices may impact decision-making in second-line/platinum-sensitive setting • Looks like we can re-use bevacizumab • If you received PARPi in front line—can you re-use? In what circumstance? – OrEO trial ongoing to assess rechallenging with PARPi • How does immunotherapy fit into the relapsed setting if used in frontline? Conclusions BRCAm=BRCA mutated; PARPi=PARP inhibitor.